European Journal of Heart Failure (2013) 15, 1245–1252

doi:10.1093/eurjhf/hft087

Left atrial expansion index predicts all-cause

mortality and heart failure admissions in dyspnoea
Shih-Hung Hsiao 1,2,3* and Kuan-Rau Chiou 1,2
1
Division of Cardiology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan, Republic of China; 2National Yang-Ming University,
School of Medicine, Taipei, Taiwan, Republic of China; and 3Chung Hwa University of Medical Technology, Taiwan, Republic of China

Received 15 March 2013; revised 13 April 2013; accepted 3 May 2013; online publish-ahead-of-print 22 May 2013

Aims The power of left atrial (LA) parameters for predicting adverse events in relatively low-risk groups is not fully understood.
This study investigated whether the LA expansion index predicts heart failure (HF) and all-cause mortality in subjects with
dyspnoea.
.....................................................................................................................................................................................
Methods Echocardiography was performed to identify causes of dypnoea in 1735 patients. The LA expansion index was calculated
and results as (Volmax – Volmin) × 100%/Volmin, where Volmax was defined as the maximal LA volume and Volmin was defined as the
minimal LA volume. The endpoints were 2-year frequencies of HF hospitalization and all-cause mortality. Over a median
follow-up of 2.7 years, 91 participants reached endpoints. Rates of adverse events were exponentially proportional to the
LA expansion index. For predicting adverse events, the LA expansion index was better than the maximal indexed LA
volume and tissue Doppler parameters. Hospitalization for HF was independently associated with age, LVEF, pulmonary
artery systolic pressure, LA expansion index, and history of prior HF. All-cause mortality was associated with age, pul-
monary artery systolic pressure, and LA expansion index. Compared with the highest quartile of the LA expansion
index, the lowest quartile had a 3.1-fold higher hazard of HF events and a 17.8-fold higher hazard of all-cause mortality.
.....................................................................................................................................................................................
Conclusions The LA expansion index predicts adverse events in patients with dyspnoea. The prognostic power of the index exceeds
that of other well-established echocardiographic parameters such as E/e’ and maximal indexed LA volume.
.....................................................................................................................................................................................
Trial registration NCT01171040.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Left atrial expansion index † Maximal indexed left atrial volume † Heart failure hospitalization † All-cause mortality

showed that the LA expansion index, which accurately reflects in-

Introduction
During ventricular diastole, the left atrium is subjected to LV pressure
after mitral valve opening. Thus, the left atrial (LA) volume mirrors
the diastolic filling of the left ventricle. As a marker of increased LV
filling pressure, recent studies show that LA volume provides a sen-
sitive morphophysiological indicator of the severity of LV dysfunction
and may also be a useful index of cardiovascular risk.1 – 6 Dilation of
the left atrium for reasons other than diastolic dysfunction, i.e. LV re-
modelling or mitral regurgitation,7 – 9 is notable because these patho-
physiological variables are associated with poor prognosis.10,11
Therefore, the contributing effects of multiple causes of impaired sur-
vival may explain the considerable prognostic power of LA volume.
Although LA volume indicates the chronicity and severity of diastolic
dysfunction, no studies have determined the exact relationship
between LA volume and LV filling pressure. The authors recently
stantaneous LV filling pressure (logarithmic correlation) in many
disease entities, including stable angina, acute myocardial infarction,
and severe mitral regurgitation, is useful for predicting AF after cor-
onary artery bypass graft surgery, heart failure (HF) rehospitalization,
and both short- and long-term mortality in ischaemic heart
disease.12 – 16 We hypothesized that the LA expansion index predicts
long-term outcome not only in patients with heart disease, but also in
relatively low-risk populations such as consecutive patients treated
for dyspnoea at a cardiovascular clinic.
Methods
Study population
Between August 2009 and April 2010, this prospective study recruited
patients aged 50 years or older who had received echocardiographic

* Corresponding author. Cardiovascular Center, Department of Internal Medicine, Kaohsiung Veterans General Hospital, 386, Da-Chung 1st Road, Kaohsiung 813, Taiwan, Republic of
China. Tel: +886 7 342 2121 ext. 2011, Fax: +886 7 345 5045, Email: h841120@gmail.com
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com.
1246
examination for the complaint of dyspnoea on their first visit to the car-
diovascular outpatient clinic of Kaohsiung Veterans General Hospital in
Kaohsiung, Taiwan. Exclusion criteria included any history of the follow-
ing: (i) mitral stenosis or prosthetic mitral valve; (ii) atrial septal abnormal-
ity (e.g. atrial septal defect or aneurysm); (iii) rhythm other than sinus
rhythm; (iv) acute HF at presentation; and (v) lung disease confirmed
by chest image, pulmonary function test, or diagnosis by a chest specialist.
The analysis also excluded patients with inadequate image quality and
patients who did not give informed consent to participate. In total,
1735 patients were enrolled for final analysis. Histories of hyperlipid-
aemia, hypertension, and smoking were recorded by the examining phy-
sicians. At the index examination, subjects were considered hypertensive
if they had high blood pressure or were currently receiving drug treat-
ment for hypertension. Diabetes mellitus was defined according to
American Diabetes Association criteria.17 At enrolment, creatinine
clearance (CCr) was estimated by the Cockroft –Gault equation, and
renal dysfunction was defined as CCr ,60 mL/min/1.73 m2.18 CAD
was defined as any history of the following: (i) myocardial infarction;
(ii) at least 70% stenosis in one or more coronary vessels on coronary
angiography; (iii) exercise-induced ischaemia indicated by treadmill
ECG or nuclear perfusion stress imaging; or (iv) coronary revasculari-
zation. Since the aim was to evaluate clinical and echocardiographic
parameters as predictors of cardiovascular events, including HF hospital-
ization, stroke, AF, and all-cause mortality during the follow-up period,
patients with rhythm other than sinus rhythm were first excluded. The
endpoints for this phase of the study were HF hospitalization and all-
cause mortality. The study protocol was approved by the institutional
review board of Kaohsiung Veterans General Hospital. Patients were
invited to participate in this study only after giving written informed
consent.
Echocardiographic measurements
Conventional echocardiographic and tissue
Doppler measurements
The LVEF was calculated by the Simpson biplane technique. Pulmonary
artery systolic pressure was estimated using Doppler echocardiography
by calculating the right ventricular to right atrial pressure gradient during
systole. Right atrial pressure, estimated on the basis of echocardiographic
characteristics of the inferior vena cava,19 was then added to the calcu-
lated gradient. The LV mass was calculated using the formula described
by Devereux and Reichek.20 The LV mass was indexed to body surface
area (BSA). Pulsed-wave tissue Doppler imaging (TDI) was performed
in apical views, and a pulsed-wave Doppler sample volume was placed
at the level of the mitral annulus over the septal and lateral borders.
The pulsed-wave TDI tracing recorded over five cardiac cycles at a
sweep speed of 100 mm/s was used for offline calculations. The
average early diastolic velocity (e’) of the septal and lateral mitral annuli
was used to estimate LV filling pressure by the E/e’ method.21 The severity
of mitral regurgitation, which was evaluated semi-quantitatively from the
area of regurgitant jet by colour Doppler, was classified as absent or trivial
(0), mild (1+), moderate (2+), or severe (3+). Diastolic dysfunction was
assessed as described previously.22,23 Based on Doppler measurements
of mitral inflow and TDI,24 diastolic function was classified into four cat-
egories: normal, mild (impaired relaxation without evidence of increased
filling pressures), moderate (pseudonormal with moderately elevated
filling pressures), and severe (restrictive with advanced reduction in com-
pliance).
Left atrial volume parameter measurements
All volume measurements were calculated by the biplane area– length
method in apical four- and two-chamber views.25 The LA volumes
were measured at two points, immediately before mitral valve opening
S.-H. Hsiao and K.-R. Chiou
(maximal LA volume or Volmax) and at mitral valve closure (minimal
LA volume or Volmin). The LA expansion index was calculated as
(Volmax – Volmin) × 100%/Volmin. In all patients, LA volumes were
indexed to BSA.16
Clinical follow-up
Patients were followed up at our cardiovascular clinic for at least 2 years.
A follow-up survey was performed to assess HF hospitalization and all-
cause mortality. Hospitalization for HF was defined as a hospital stay of
at least one night for treatment of a clinical syndrome with at least two
of the following symptoms: paroxysmal nocturnal dyspnoea, orthop-
noea, elevated jugular venous pressure, pulmonary rales, a third heart
sound, cardiomegaly on chest radiography, or pulmonary oedema on
chest radiography. These clinical signs and symptoms might have repre-
sented a clear change from the normal clinical state of the patient and
might have been accompanied by either failing cardiac output, as deter-
mined by peripheral hypoperfusion (in the absence of other causes
such as sepsis or dehydration), or peripheral or pulmonary oedema re-
quiring treatment with i.v. diuretics, inotropes, or vasodilators. Support-
ive documentation of a decreased cardiac index, an increased PCWP,
decreasing oxygen saturation, and end-organ hypoperfusion, if available,
was included in the adjudication. Follow-up included medical record
reviews and patient interviews. Medical assistants checked medical
records once every 3 months. For patients lost to follow-up, assistants
contacted and interviewed patients by telephone, or, if necessary, by vis-
iting patients at their homes. The certification of death was based on
death records, death certificates, and hospital medical records.
Interobserver variability
In the first 100 enrolled cases, Volmax and Volmin were measured by two
independent observers. Interobserver variability was calculated as the
difference between the values obtained by the two observers divided
by the mean. Interobserver difference and variability were 3.0 + 4.9
mL/m2 and 5.1 + 8.4% for Volmax, and 2.7 + 4.2 mL/m2 and 6.0 +
8.9% for Volmin, respectively. Therefore, the interobserver variability in
LA expansion index measurements was 5.9 + 7.8%.
Statistical analysis
The SPSS software was used for all statistical analyses. Baseline character-
istics and echocardiographic parameters were analysed according to
adverse events. All continuous variables were presented as means +
SD. A P-value of ,0.05 was considered statistically significant. Clinical
characteristics were compared by x2 analysis of categorical variables.
Group differences were analysed by analysis of variance and post-hoc
tests for unpaired data. Cox proportional hazards regression was used
for examining the association between the LA expansion index and
adverse events, univariately and while controlling for baseline character-
istics. Rates of adverse events were compared across LA expansion index
quartiles by multivariate Cox regression. The independent prognostic
value of the LA expansion index was determined by multivariate
models adjusted for covariates showing significant (P , 0.05) associa-
tions with events. The area under the receiver operating characteristic
(ROC) curve (AUC) was used to evaluate the sensitivity and specificity
of predictors of adverse events. The C-statistic was calculated to
compare the conventional maximal indexed LA volume, TDI, and LA
expansion index in terms of accuracy in predicting adverse events.
LA expansion index as long-term predictor of adverse events 1247

Results characteristics and echocardiographic parameters according to

adverse events. Adverse events were associated with the following
Clinical characteristics patient characteristics: advanced age, male gender, hypertension, dia-
betes, current smoking status, CAD, mitral regurgitation severity,
The median follow-up period was 2.7 years. Of the 1735 patients
history of prior HF, renal dysfunction, pulmonary hypertension, LV
included in the final analysis, 65 (3.7%) had HF events with hospital-
dilation, high LV mass index, advanced diastolic dysfunction (pseudo-
ization and 51 (2.9%) died. Of 51 mortality events, 8 were related
normal/restrictive) and LV systolic dysfunction, elevated E/e’, high
to malignancies and 10 were related to infection or sepsis. Ninety-
minimal/maximal indexed LA volume, and low LA expansion index.
one participants (5.2%) reached endpoints. Table 1 lists their basic

Table 1 Patient characteristics and echocardiographic parameters according to adverse events

No events (n 5 1644) Events (n 5 91) P-values

...............................................................................................................................................................................
Age (years) 57 + 21 69 + 12 ,0.0001
Male gender (%) 905 (55.0%) 61 (67.0%) ,0.0001
Hypertension (%) 649 (39.5%) 53 (58.2%) ,0.0001
Systolic blood pressure (mmHg) 130 + 23 138 + 42 0.001
Diastolic blood pressure (mmHg) 82 + 23 87 + 24 0.092
Diabetes (%) 238 (14.5%) 33 (36.3%) ,0.0001
Current smoker (%) 363 (22.1%) 41 (45.1%) ,0.0001
SL voltage criteria for LVH 39 (2.4%) 4 (4.4%) ,0.0001
CAD (%) 119 (7.2%) 26 (28.6%) ,0.0001
MR .moderate severity (%) 166 (10.1%) 43 (47.3%) ,0.0001
Prior heart failure (%)a 30 (1.8%) 22 (24.2%) ,0.0001
Renal dysfunction (%) 218 (13.3%) 34 (37.4%) ,0.0001
Estimated CCr (mL/min/1.73 m2) 78 + 21 62 + 28 ,0.0001
Medications ,0.0001
Aspirin (%) 255 (15.5%) 42 (46.2%)
Statin (%) 153 (9.3%) 45 (49.2%)
ACEI (%) 220 (13.4%) 36 (40%)
ARB (%) 199 (12.1%) 20 (22.0%)
Beta-blocker (%) 193 (11.7%) 32 (35.2%)
Heart rate (b.p.m.) 70 + 12 78 + 15 ,0.0001
Diastolic function ,0.0001
Normal 802 (48.8%) 13 (14.3%)
Impaired relaxation 722 (43.9%) 34 (37.4%)
Pseudonormal 90 (5.5%) 22 (24.2%)
Restrictive 30 (1.8%) 22 (24.2%)
LVIDd (mm) 49 + 4 54 + 7 ,0.0001
E velocity (cm/s) 73 + 22 90 + 34 ,0.0001
A velocity (cm/s) 73 + 23 72 + 27 0.596
E-deceleration time (ms) 225 + 64 196 + 68 0.001
LV mass index (g/m2) 123 + 34 155 + 41 ,0.0001
PASP (mmHg) 28 + 9 45 + 13 ,0.0001
LVEF (%) 59 + 8 45 + 12 ,0.0001
Max indexed LAV (mL/m2) 26 + 14 40 + 17 ,0.0001
Min indexed LAV (mL/m2) 13 + 10 27 + 16 ,0.0001
E/e’ 10.0 + 4.3 15.4 + 6.7 ,0.0001
LA expansion index (%) 139 + 81 61 + 31 ,0.0001

A, peak late-diastolic velocity of mitral inflow; ACEI, ACE inhibitor; CCr, creatine clearance; E, peak early-diastolic velocity of mitral inflow; e’, average early-diastolic velocity of septal
and lateral mitral annuli; LA, left atrial; LAV, left atrial volume; LVIDd, left ventricular end-diastolic internal diameter; MR, mitral regurgitation; PASP, pulmonary arterial systolic
pressure; SL voltage criteria for LVH, Sokolow–Lyon voltage criteria for left ventricular hypertrophy with the definition of sum of the amplitudes of S wave on V1 and R wave on V5 or
V6 .3.5 mV
a
History of heart failure: previous admission to cardiovascular department with diagnosis of heart failure.
1248 S.-H. Hsiao and K.-R. Chiou

Outcome predictors pressure, and LA expansion index (Table 2). Multivariate analysis of
Univariate and multivariate analyses based on Cox proportional HF hospitalization showed that none of the following was an independ-
hazards models revealed that HF hospitalization is significantly asso- ent predictor of events: diastolic function grade, LV mass index, CAD,
ciated with age, history of prior HF, LVEF, pulmonary artery systolic diabetes, hypertension, mitral regurgitation, renal dysfunction, or E/e’.

Table 2 Univariate and multivariate predictors of heart failure events

Variables Univariate analysis Multivariate analysis

Hazard ratio (95% CI) P-values Hazard ratio (95% CI) P-values
...............................................................................................................................................................................
Age (years) 1.007 (1.004–1.011) ,0.0001 1.008 (1.002–1.014) per 1 year increase 0.006
CAD 5.389 (3.182–9.126) ,0.0001 1.321 (0.738–2.446) 0.378
Prior heart failure 7.917 (4.565–24.378) ,0.0001 3.521 (1.714–7.832) ,0.0001
Male gender 2.257 (1.298–3.925) 0.004 0.926 (0.542–1.672) 0.776
Diabetes 3.651 (2.215–6.017) ,0.0001 1.028 (0.566–1.866) 0.928
Hypertension 2.226 (1.355–3.656) 0.002 1.053 (0.594–1.865) 0.86
Renal dysfunction 4.716 (2.886–7.705) ,0.0001 1.365 (0.791–2.357) 0.264
LVIDd (mm) 1.163 (1.128–1.199) ,0.0001 0.987 (0.936–1.041) 0.638
MR 3.881 (1.869–8.057) ,0.0001 0.959 (0.695–1.323) per 1 grade increase 0.799
Diastolic function grade 6.269 (1.568–18.126) 0.001 1.085 (0.706–1.668) per 1 grade increase 0.711
LVEF (%) 0.892 (0.877–0.907) ,0.0001 0.941 (0.911–0.973) per 1% increase 0.001
PASP (mmHg) 1.089 (1.075–1.103) ,0.0001 1.045 (1.020–1.071) per 1 mmHg increase ,0.0001
Maximal indexed LAV (mL/m2) 1.025 (1.020–1.031) ,0.0001 1.008 (0.959–1.059) per 1 mL/m2 increase 0.754
Minimal indexed LAV (mL/m2) 1.034 (1.028–1.040) ,0.0001 1.005 (0.920–1.094) per 1 mL/m2 increase 0.666
LA expansion index (%) 0.955 (0.946–0.964) ,0.0001 0.970 (0.956–0.985) per 1% increase ,0.0001
E/e’ 1.146 (1.115–1.179) ,0.0001 0.989 (0.916–1.081) per 1 unit increase 0.173
LV mass index (g/m2) 1.012 (1.010–1.015) ,0.0001 0.996 (0.988–1.005) per 1 g/m2 increase 0.385

CI, confidence interval; E, peak early-diastolic velocity of mitral inflow; e’, average early-diastolic velocity of septal and lateral mitral annuli; LA, left atrial; LAV, left atrial volume;
LVIDd, left ventricular end-diastolic internal diameter; MR, mitral regurgitation; PASP, pulmonary arterial systolic pressure.

Table 3 Univariate and multivariate predictors of all-cause mortality

Variables Univariate analysis Multivariate analysis

Hazard ratio (95% CI) P-values Hazard ratio (95% CI) P-values
...............................................................................................................................................................................
Age (years) 1.007 (1.003–1.011) 0.001 1.007 (1.000– 1.014) per 1 year increase 0.038
CAD 3.694 (1.934–7.056) ,0.0001 1.121 (0.864– 3.143) 0.218
Prior heart failure 8.215 (3.998–16.880) ,0.0001 1.900 (0.801– 4.504) 0.145
Male gender 1.045 (0.601–1.819) 0.876
Diabetes 2.922 (1.633–5.231) ,0.0001 0.931 (0.450– 1.928) 0.848
Hypertension 1.943 (1.116–3.381) 0.019 1.389 (0.705– 2.738) 0.342
Renal dysfunction 3.696 (2.095–6.520) ,0.0001 1.324 (0.688– 2.549) 0.4
LVIDd (mm) 1.123 (1.080–1.167) ,0.0001 0.975 (0.914– 1.040) 0.446
MR 2.143 (1.702–2.699) ,0.0001 0.957 (0.837– 1.377) per 1 grade increase 0.512
Diastolic function grade 3.075 (2.347–4.030) ,0.0001 1.184 (0.707– 1.984) per 1 grade increase 0.521
LVEF (%) 0.916 (0.898–0.934) ,0.0001 0.982 (0.945– 1.020) per 1% increase 0.351
PASP (mmHg) 1.086 (1.068–1.103) ,0.0001 1.052 (1.024– 1.080) per 1 mmHg increase ,0.0001
Maximal indexed LAV (mL/m2) 1.023 (1.016–1.030) ,0.0001 1.012 (0.962– 1.064) per 1 mL/m2 increase 0.652
Minimal indexed LAV (mL/m2) 1.032 (1.024–1.039) ,0.0001 0.964 (0.900– 1.033) per 1 mL/m2 increase 0.298
LA expansion index (%) 0.969 (0.961–0.978) ,0.0001 0.973 (0.958– 0.989) per 1% increase 0.001
E/e’ 1.139 (1.102–1.176) ,0.0001 1.007 (0.953– 1.064) per 1 unit increase 0.805
LV mass index (g/m2) 1.011 (1.008–1.015) ,0.0001 1.004 (0.994– 1.014) per 1 g/m2 increase 0.423

CI, confidence interval; E, peak early-diastolic velocity of mitral inflow; e’, average early-diastolic velocity of septal and lateral mitral annuli; LA, left atrial; LAV, left atrial volume;
LVIDd, left ventricular end-diastolic internal diameter; MR, mitral regurgitation; PASP, pulmonary arterial systolic pressure.
LA expansion index as long-term predictor of adverse events 1249

All-cause mortality is significantly associated with age, pulmonary

P-value

.............................................................................................................................................................................................................................................
artery systolic pressure, and LA expansion index (Table 3).

P-value
0.811
0.233
0.037

0.965
0.597
0.005
Outcomes by left atrial expansion index
quartile
Supplementary Table, patient characteristics and echocardiographic

Adjusted HR (95% CI)a

parameters by quartiles of left atrial expansion index. The HF hospi-

17.750 (2.376– 132.628)

Adjusted HR (95% CI)b

1.063 (0.106– 17.018)

1.871 (0.183– 19.104)
1.182 (0.293– 4.767)
2.226 (0.811– 8.142)
3.108 (1.137– 7.462)
talization rates increased from 3.5 per 1000 person-years in the
highest quartile (Q1) of the LA expansion index to 35.1 per 1000
person-years in the lowest quartile (Q4) (Table 4). The rate of
events apparently increased exponentially as the LA expansion
indices decreased. Figure 1 shows the apparently exponential correl-
ation of each LA expansion index decile with 2-year adverse event
rates. Compared with Q1, Q4 showed an unadjusted hazard ratio
of 10.664 for HF hospitalization. After adjustment for other
multivariate-independent cofactors (age, LVEF, pulmonary artery

,0.0001

,0.0001
P-value
systolic pressure, E/e’, and history of prior HF), Q4 still had a signifi-

0.994
0.009

0.335
0.138
P-value
cantly higher (3.108-fold higher) hazard ratio for HF hospitalization
compared with Q1 (P ¼ 0.037). Compared with Q1, Q4 showed
an unadjusted hazard ratio of 44.923 for all-cause mortality. After ad-

Table 4 Unadjusted and adjusted associations of quartiles of left atrial expansion index with adverse events
justment for other multivariate-independent cofactors (age and pul-
monary artery systolic pressure), Q4 had a 17.75-fold hazard ratio for

Unadjusted HR (95% CI)

all-cause mortality compared with Q1 (P ¼ 0.005).

Unadjusted HR (95% CI)

44.923 (6.183– 226.405)

1.056 (1.343– 11.532)
10.664 (3.419– 31.024)

3.046 (0.317– 29.283)

5.069 (0.592– 43.389)
1.003 (0.256– 4.013)
Comparison of prognostic power between
maximal left atrial volume and left atrial
expansion index
For predicting further HF hospitalization, comparison of the
C-statistics for E/e’, maximal indexed LA volume, and LA expansion
index showed that the LA expansion index was the best predictor
of further HF hospitalization (Figure 2A; C-statistics for E/e’ vs.
maximal indexed LA volume vs. LA expansion index were 0.741 vs.
(per 1000 person-years)
Heart failure event

(per 1000 person-years)

0723 vs. 0.886, respectively, for HF hospitalization). The E/e’ and

All-cause mortality rate

Adjusted by age, prior history of heart failure, LVEF, pulmonary artery systolic pressure, and E/e’
maximal indexed LA volume had similar power to predict HF
events. An LA expansion index ,79% was the best predictor of
HF hospitalization (sensitivity 82% and specificity 80%) although
E/e’ . 11 (sensitivity 71% and specificity 70%) and maximal
indexed LA volume .30.8 mL/m2 (sensitivity 74% and specificity
3.5
3.5

0.9
2.6
4.4
14.0
35.1
14.2

36.8
11.2

74%) were also reliable predictors. For predicting all-cause mortality,

the LA expansion index was also better than E/e’ and maximal
indexed LA volume (Figure 2b; C-statistics for E/e’ vs. maximal
indexed LA volume vs. LA expansion index were 0.735 vs. 0757 vs.
No. of events

0.827, respectively). An LA expansion index ,82.7% was the best

No. of events

Adjusted by age and pulmonary artery systolic pressure.

CI, confidence interval; HR, hazard ratio; LA, left atrial.

predictor of adverse events including HF hospitalization and all-cause

mortality (sensitivity 75% and specificity 76%). Supplementary Figure,
4
4

1
3
5
16
41
65

42
51

Kaplan-Meier curve according to left atrial expansion index 82.7%.

Discussion
Quartile 1 (174– 566%)
Quartile 2 (117– 174%)

Quartile 1 (174– 566%)

Quartile 2 (117– 174%)
LA expansion index

Quartile 3 (93– 117%)

Quartile 3 (93– 117%)

In previous studies, the authors showed that the ratio of change in LV

Quartile 4 (21– 93%)

Quartile 4 (21– 93%)

LA expansion index

filling pressure has a logarithmic correlation with the change in LA

volume from minimal to maximal (LA expansion index).12 – 16 There-
fore, the LA expansion index accurately reflects diastolic properties.
Compared with LA volume, LA function has a stronger independent
Total

Total

correlation with LV diastolic dysfunction and arterial stiffness26 in

b
a

many categories of patients; these data support the hypothesis that,

1250 S.-H. Hsiao and K.-R. Chiou

Figure 1 Apparent exponential correlation between deciles of the left atrial (LA) expansion index and rate of 2-year adverse events.

Figure 2 (A) The receiver operating characteristic curves for diastolic parameters for predicting 2-year heart failure hospitalization. (B) The re-
ceiver operating characteristic curves for diastolic parameters for predicting 2-year all-cause mortality. LA, left atrial; LAV, left atrial volume.
LA expansion index as long-term predictor of adverse events
for assessing HF, LA dysfunction is more sensitive than morphological
parameters. For these reasons, the LA expansion index is superior to
LA volume for assessing HF hospitalization. Tissue Doppler parameters,
particularly E/e’, are reportedly associated with elevated LV filling pres-
sure and are useful late outcome predictors for many cardiovascular dis-
eases.27,28 Nevertheless, tissue Doppler provides regional measures of
′
systolic and diastolic function. When E/e is used to assess some disease
entities with only regional myocardial impairment, such as CAD, it infers
that regional parameters obtained by tissue Doppler are not sufficiently
precise measures of global LV function.
Viewing the left atrium as a balloon, one cannot estimate internal
pressure by the size of the balloon. However, if you put a constant
volume of air with constant pressure into a balloon and observe
the change of balloon morphology, you can speculate on the original
pressure inside the balloon. By non-invasive echocardiographic
measurement, an expansion index is produced by predicting the ori-
ginal pressure by volume change after constant air supply and assum-
ing the filling air pressure is constant. While the internal pressure of a
balloon is very high, you can determine two things: (i) air with relative-
ly low pressure has difficulty entering the balloon; and (ii) after supply
of air, the volume change of the balloon is not as obvious as you
predict. The first indicates filling dysfunction; for the heart, it indicates
vulnerability to HF. The second can be simply estimated as the
balloon expansion index. It is the basic concept of the LA expansion
index to predict a HF event. Regarding denominators used in the
equation of the LA expansion index, we prefer Volmin. According
to the report of Russo et al.,29 the increase in Volmin with worsening
diastolic function is more pronounced than that of Volmax, and Volmin
is better correlated with E/e’ than Volmax. The relationship between
Volmax and LV diastole may be confounded by the LV systolic func-
tion. On the other hand, the relationship between Volmin and LV dia-
stolic function appears to be more direct, as in end-diastole the mitral
valve is open and the left atrium is directly exposed to the LV pres-
sure. Thus, the LA expansion index was calculated as (Volmax –
Volmin) × 100%/Volmin, although the LA emptying fraction using
Volmax as the denominator is useful for predicting post-operative
AF.30 Based on two reasons, the LA ejection fraction is also not
well suited to assessing prognosis. First, it cannot be measured in
patients with atrial arrhythmia, particularly atrial flutter and AF. Sec-
ondly, tachycardia, particularly a heart rate . 110 b.p.m., causes the
merging of T and P waves on the ECG, which makes the measure-
ments of LA ejection fraction impossible.
Even after adjusting other covariates, the LA expansion index was
independently associated with adverse events (Tables 2 and 3). The
results in this study therefore show that the LA expansion index is
a valuable tool for stratifying risk of adverse events in a relatively
low-risk population. These results are consistent with our previous
report that the LA expansion index is applicable for predicting
rates of 12-month events in high-risk cohorts such as patients with
acute coronary syndrome.12 The index is also useful for predicting
AF after coronary artery bypass graft surgery.13 Therefore, the
broad clinical applications of the LA expansion index make it valuable
for assessing patient prognosis in varying populations.
Limitations of the study
This study has several limitations. First, this single-centre study en-
rolled patients with dyspnoea from the cardiovascular outpatient
1251
clinic at a single institute. Since this population was not a true
low-risk population free of cardiovascular disease, further large-scale
studies are needed to confirm the applicability of the results to the
general population of extremely low-risk individuals. In addition,
because data collection in this study did not include BNP and
NT-proBNP, we could not determine whether a cardiovascular
problem was the main cause of dyspnoea in the enrolled patients.
Nevertheless, the final results confirmed the prognostic value and
practicality of the LA expansion index in a mixed cohort of all-cause
dyspnoea patients. Secondly, only a single measure of the resting LA
expansion index was evaluated. Other echocardiographic measures
of LA function, including segmental atrial function assessment, strain,
strain rate, and atrial response to exercise, were not examined.
Thirdly, the results of this study should be interpreted with caution
because of its very low interobserver variability (5–6%) in compari-
son with other studies (e.g. 10% in Ujino et al. 25). However, since the
analysis was limited to a population of Taiwanese patients, a contrib-
uting factor may have been the better quality echocardiographic
images as a result of the relatively smaller body size and thinner
chest wall in this population in comparison with western populations.
Conclusions
The rates of adverse events are exponentially proportional to the LA
expansion index. The prognostic power of the index exceeds that of
other well-established echocardiographic parameters such as E/e’
and maximal indexed LA volume. The LA expansion index is useful
for long-term risk stratification in relatively low-risk populations.
Supplementary material
Supplementary material is available at European Journal of Heart Failure
online.
Funding
Kaohsiung Veterans General Hospital (VGHKS98-CT6-07).
Conflict of interest: none declared.
References
1. Appleton CP, Galloway JM, Gonzales MS, Gaballa M, Basnight MA. Estimation of left
ventricular filling pressure using two-dimensional and Doppler echocardiography in
adult patients with cardiac disease. Additional value of analyzing left atrial size, left
atrial ejection fraction and the difference in duration of pulmonary venous and
mitral flow velocity at atrial contraction. J Am Coll Cardiol 1993;22:1972 –1982.
2. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morpho-
physiologic expression of left ventricular diastolic dysfunction and relation to cardio-
vascular risk burden. Am J Cardiol 2002;90:1284 –1289.
3. Tsang TS, Barnes ME, Gersh BJ, Takemoto Y, Rosales AG, Bailey KR, Seward JB. Pre-
diction of risk for first age-related cardiovascular events in an elderly population: the
incremental value of echocardiography. J Am Coll Cardiol 2003;42:1199 –1205.
4. Moller JE, Hillis GS, Oh JK, Seward JB, Reeder GS, Wright RS, Park SW, Bailey KR,
Pellikka PA. Left atrial volume: a powerful predictor of survival after acute myocardial
infarction. Circulation 2003:107:2207 – 2212.
5. Shuai XX, Chen YY, Lu YX, Su GH, Wang YH, Zhao HL, Han J. Diagnosis of heart
failure with preserved ejection fraction: which parameters and diagnostic strategies
are more valuable? Eur J Heart Fail 2011;13:737 –745.
6. Lim TK, Dwivedi G, Hayat S, Majumdar S, Senior R. Independent value of left atrial
volume index for the prediction of mortality in patients with suspected heart
failure referred from the community. Heart 2009;95:1172 –1178.
7. Popescu BA, Macor F, Antonini-Canterin F, Giannuzzi P, Temporelli PL, Bosimini E,
Gentile F, Maggioni AP, Tavazzi L, Piazza R, Ascione L, Stoian I, Cervesato E,
Nicolosi GL; GISSI-3 Echo Substudy Investigators. Left atrium remodeling after
1252
acute myocardial infarction (results of the GISSI-3 Echo Substudy). Am J Cardiol 2004;
93:1156 –1159.
8. Rossi A, Golia G, Gasparini G, Prioli MA, Anselmi M, Zardini P. Left atrial filling
volume can be used to reliably estimate the regurgitant volume in mitral regurgita-
tion. J Am Coll Cardiol 1999;33:212 –217.
9. Sanfilippo AJ, Abascal VM, Sheehan M, Oertel LB, Harrigan P, Hughes RA,
Weyman AE. Atrial enlargement as a consequence of atrial fibrillation. A prospective
echocardiographic study. Circulation 1990;82:792 –797.
10. Wong M, Staszewsky L, Latini R, Barlera S, Glazer R, Aknay N, Hester A, Anand I,
Cohn JN. Severity of left ventricular remodeling defines outcomes and response
to therapy in heart failure: valsartan heart failure trial (Val-HeFT) echocardiographic
data. J Am Coll Cardiol 2004;43:2022 –2027.
11. Blondheim DS, Jacobs LE, Kotler MN, Costacurta GA, Parry WR. Dilated cardiomy-
opathy with mitral regurgitation: decreased survival despite a low frequency of ven-
tricular thrombus. Am Heart J 1991;122:763 –771.
12. Hsiao SH, Chiou KR, Porter TR, Huang WC, Lin SK, Kuo FY, Cheng CC, Lin KL,
Lin SL. Left atrial parameters in the estimation of left ventricular filling pressure
and prognosis in patients with acute coronary syndrome. Am J Cardiol 2011;107:
1117 –1124.
13. Wang WH, Hsiao SH, Lin KL, Wu CJ, Kang PL, Chiou KR. Left atrial expansion index
for predicting atrial fibrillation and in-hospital mortality after coronary artery bypass
graft surgery. Ann Thorac Surg 2012;93:796 –803.
14. Hsiao SH, Lin KL, Chiou KR. Comparison of left atrial volume parameters in detect-
ing left ventricular diastolic dysfunction versus tissue Doppler recordings. Am J
Cardiol 2012;109:748 – 755.
15. Hsiao SH, Chiou KR, Lin KL, Lin SK, Huang WC, Kuo FY, Cheng CC, Liu CP. Left atrial
distensibility and E/e’ for estimating left ventricular filling pressure in patients with
stable angina. A comparative echocardiography and catheterization study. Circ J
2011;75:1942 – 1950.
16. Hsiao SH, Huang WC, Lin KL, Chiou KR, Kuo FY, Lin SK, Cheng CC. Left atrial dis-
tensibility and left ventricular filling pressure in acute versus chronic severe mitral
regurgitation. Am J Cardiol 2010;105:709 –715.
17. American Diabetes Association: clinical practice recommendations 1997. Diabetes
Care 1997;20:suppl 1:S1-70.
18. Dries DL, Exner DV, Domanski MJ, Greenberg B, Stevenson LW. The prognostic
implications of renal insufficiency in asymptomatic and symptomatic patients with
left ventricular systolic dysfunction. J Am Coll Cardiol 2000;35:681 –689.
S.-H. Hsiao and K.-R. Chiou
19. Ommen SR, Nishimura RA, Hurrell DG, Klarich KW. Assessment of right atrial pres-
sure with 2-dimentional and Doppler echocardiography: a simultaneous catheter-
ization and echocardiographic study. Mayo Clin Proc 2000;75:24 –29.
20. Devereux RB, Reichek N. Echocardiographic determination of left ventricular mass
in man: anatomic validation of the method. Circulation 1977;55:613 –618.
21. Rivas-Gotz C, Manolios M, Thohan V, Nagueh SF. Impact of left ventricular ejection
fraction on estimation of left ventricular filling pressure using tissue Doppler and flow
propagation velocity. Am J Cardiol 2003;91:780 –784.
22. Bursi F, Weston SA, Redfield MM, Jacobsen SJ, Pakhomov S, Nkomo VT,
Meverden RA, Roger VL. Systolic and diastolic heart failure in the community.
JAMA 2006;296:2209 –2216.
23. Redfield MM, Jacobsen SJ, Burnett JC Jr., Mahoney DW, Bailey KR, Rodeheffer RJ.
Burden of systolic and diastolic ventricular dysfunction in the community: appreciat-
ing the scope of the heart failure epidemic. JAMA 2003;289:194–202.
24. Nagueh SF, Appleton CP, Gillebert TC, Marino PN, Oh JK, Smiseth OA,
Waggoner AD, Flachskampf FA, Pellikka PA, Evangelisa A. Recommendations for
the evaluation of left ventricular diastolic function by echocardiography. Eur J Echo-
cardiogr 2009;10:165 –193.
25. Ujino K, Barnes ME, Cha SS, Langins AP, Bailey KR, Seward JB, Tsang TS. Two-
dimensional echocardiographic methods for assessment of left atrial volume. Am J
Cardiol 2006;98:1185 –1188.
26. Miyoshi H, Mizuguchi Y, Oishi Y, Iuchi A, Nagase N, Ara N, Oki T. Early detection of
abnormal left atrial– left ventricular-arterial coupling in preclinical patients with car-
diovascular risk factors: evaluation by two-dimensional speckle-tracking echocardi-
ography. Eur J Echocardiogr 2011;12:431 –439.
27. Nagueh SF, Middleton KJ, Kopelen HA, Zoghbi WA, Quiñones MA. Doppler tissue
imaging: a noninvasive technique for evaluation of left ventricular relaxation and es-
timation of filling pressure. J Am Coll Cardiol 1997;30:1527 –1533.
28. Hillis GS, Møller JE, Pellikka PA, Gersh BJ, Wright RS, Ommen SR, Reeder GS, Oh JK.
′
Noninvasive estimation of left ventricular filling pressure by E/e is a powerful pre-
dictor of survival after acute myocardial infarction. J Am Coll Cardiol 2004;43:
360 –367.
29. Russo C, Jin Z, Homma S, Rundek T, Elkind MS, Sacco RL, Di Tullio MR. Left atrial
minimum volume and reservoir function as correlates of left ventricular diastolic
function: impact of left ventricular systolic function. Heart 2012;98:813–820.
30. Raman T, Roistacher N, Liu J, Zhang H, Shi W, Thaler HT, Amar D. Preoperative left
atrial dysfunction and risk of postoperative atrial fibrillation complicating thoracic
surgery. J Thorac Cardiovasc Surg 2012;143:482 –487.