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Left Atrial Volume Index Over Late Diastolic Mitral Annulus Velocity
(LAVi/A′) Is a Useful Echo Index to Identify Advanced Diastolic Dysfunction
and Predict Clinical Outcomes
Article in Clinical Cardiology · February 2011
DOI: 10.1002/clc.20850 · Source: PubMed
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Hae-Ok Jung
Jinsoo Min
Seoul St. Mary's Hospital, Catholic University of Korea
Catholic University of Korea
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Clinical Investigations
Left Atrial Volume Index Over Late Diastolic
Mitral Annulus Velocity (LAVi/A) Is a Useful
Echo Index to Identify Advanced Diastolic
Dysfunction and Predict Clinical Outcomes
Address for correspondence:
Hae-Ok Jung, MD
Division of Cardiology,
Department of Internal Medicine
Seoul St. Mary’s Hospital,
College of Medicine
The Catholic University of Korea
505 Banpo-Dong, Seocho-Gu
Seoul, South Korea
[email protected]
Hun-Jun Park, MD; Hae Ok Jung, MD; Jinsoo Min, MD; Mahn Won Park, MD; Chan
Seok Park, MD; Dong Il Shin, MD; Woo-Seung Shin, MD; Pum Joon Kim, MD;
Ho-Joong Youn, MD; Ki-Bae Seung, MD
Division of Cardiology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College
of Medicine, The Catholic University of Korea, Seoul, South Korea
Background: Combined interpretation of late diastolic mitral annulus velocity (A ) with left atrial volume index
(LAVi) may have additional benefits in the assessment of diastolic dysfunction.
Hypothesis: The LAVi/A ratio may be useful in the identifying advanced diastolic dysfunction (ADD) and
predicting clinical outcomes in patients with dyspnea.
Methods: We enrolled 395 consecutive patients hospitalized with dyspnea (New York Heart Association
class II–IV) and performed transthoracic Doppler echocardiography and B-type natriuretic peptide (BNP)
measurement. LAVi/A values were evaluated in terms of diagnosing ADD and predicting clinical outcome.
Results: On the receiver operation characteristic curve analysis for the determination of ADD, the area under
the curves of LAVi/A in the entire population was comparable to those of BNP (0.94 vs 0.93, P = 0.845)
and mitral E/E (0.94 vs 0.93, P = 0.614) and higher than that of LAVi (0.94 vs 0.87; P = 0.014). A LAVi/A
of 4.0 was the best cut-off value to identify ADD. During a median follow-up of 31.9 months (range, 0.3 to
45.7 months), the group with LAVi/A ≥4.0 had a higher incidence of primary composite outcomes (cardiac
death and/or rehospitalization for heart failure) than the group with LAVi/A <4.0 (25.0% vs 3.3%, P < 0.001).
LAVi/A ≥4.0 was an independent predictor of clinical outcomes (odds ratio, 3.245; 95% confidence interval,
1.386–7.598; P = 0.007).
Conclusions: As a new echo index, LAVi/A is a useful parameter to identify ADD and predict clinical outcomes
in patients with dyspnea.
Introduction
The conventional diastolic dysfunction grading system
using transmitral Doppler and mitral annular tissue Doppler
data is useful in the assessment and prediction of a
patient’s symptoms, diagnosis, treatment, and prognosis.
Patients with pseudonormal and restrictive physiology have
elevated left ventricular (LV) filling pressure, decreased LV
compliance, and poorer prognosis compared to those with
mild diastolic dysfunction.1 – 3 However, it is impossible to
categorize all patients into only 4 categorical grades, and
borderline zones exist.
The early diastolic transmitral velocity/early diastolic
mitral annular velocity ratio (E/E ) and left atrial volume index (LAVi) are well-validated echo indices. E/E
correlates well with LV filling pressure and pulmonary capillary wedge pressure (PCWP).4 – 6 LAVi reflects chronic
diastolic dysfunction caused by decreased LV compliance.7,8
The authors have no funding, financial relationships, or conflicts
of interest to disclose.
124
Clin. Cardiol. 34, 2, 124–130 (2011)
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
However, there is no echo index that accurately reflects LV
compliance and filling pressure simultaneously.
We have invented a new echo index, left atrial volume
index to late diastolic mitral annular tissue velocity ratio
(LAVi/A ). A refers to late diastolic myocardial velocity of
passive distension due to left atrial (LA) contraction. As
LV compliance is decreased, A is decreased, and LAVi
progressively increases.9 The information provided by the
A and LAVi parameters may have an additional benefit in
the assessment of diastolic dysfunction.
In this study, we assessed the clinical usefulness of the
LAVi/A ratio to identify advanced diastolic dysfunction
(ADD) and predict clinical outcomes in patients with
dyspnea.
Methods
Subjects
We enrolled 395 consecutive patients hospitalized with dyspnea (New York Heart Association class II-IV) and performed
transthoracic Doppler echocardiography for the evaluation
Received: August 7, 2010
Accepted with revision: September 22, 2010
of dyspnea at Seoul St. Mary’s Hospital, Catholic University
of Korea, between November 2005 and December 2006.
Patients who had significant mitral valve diseases, atrial
arrhythmia, congenital heart disease, or a history of cardiac surgery or permanent pacemaker implantation were
excluded. Significant mitral valve disease was defined as
more than moderate mitral valve stenosis or regurgitation on transthoracic echocardiography. Atrial arrhythmia
was defined as atrial fibrillation, atrial flutter, or other documented and/or treated atrial rhythm abnormalities. Patients
with renal insufficiency (serum creatinine ≥ 2.5 mg/dL)
were also excluded due to potential confounding of plasma
B-type natriuretic peptide (BNP) levels.
Clinical data were obtained from a comprehensive review
of the medical records using established criteria for
hypertension, diabetes mellitus, hyperlipidemia, congestive
heart failure (CHF), and myocardial infarction. All subjects
gave written informed consent to participate in the study.
The institutional review board of Seoul St. Mary’s Hospital,
Catholic University of Korea, approved the study protocol.
Doppler and 2-Dimensional Echocardiography
Comprehensive echocardiography was performed using
commercially available ultrasound systems (Vivid 7, GE;
Vingmed Ultrasound, Horton, Norway; Sequoia 512,
Acuson, Mountain View, CA). Standard M-mode and
2-dimensional measurements were taken according to the
guidelines of the American Society of Echocardiography.10
LV ejection fraction was measured by the quantitative
2-dimensional biplane modified Simpson method from a
4- and 2-chamber view. LV end-diastolic and LV end-systolic
dimensions were measured by M-mode and indexed to
body surface area. The following pulsed-wave Doppler
measurements were obtained in the apical view with
the sample volume at the tip of the mitral valve and
pulmonary vein: maximal early (E) and late (A) transmitral
velocities, E wave deceleration time, A wave time duration,
systolic peak of pulmonary venous flow, diastolic peak of
pulmonary venous flow, and peak of atrial reverse flow
and its duration. Tissue Doppler measurements were also
performed at the septal mitral annulus, and systolic peak
velocity (S ), early diastolic tissue velocity (E ), and late
diastolic tissue velocity (A ) were obtained. The diastolic
functional profile of each patient was categorized into
normal, impaired relaxation, pseudonormal, or restrictive
physiology (reversible and irreversible) using a previously
published and validated method.11 Pseudonormal and
restrictive physiologies (reversible and irreversible) were
considered as ADD.3
The 2-dimensional maximal LA volume was determined
based on the apical 2- and 4-chamber views at end-systole
without foreshortening, using a biplane modified Simpson’s
method excluding the LA appendage and pulmonary vein
confluences. Each LA volume was indexed by body surface
area. Digital echocardiographic data containing a minimum
of 3 consecutive beats were acquired and transferred to a
server for storage and were interpreted by 2 independent
cardiologists blinded to each other’s reading. In all patients,
LAVi/A was measured as shown in Figure 1 and compared
with E/E and LAVi.
Figure 1. Representative samples of LA volume index over A (LAVi/A ) in patients with mild diastolic dysfunction (A) and moderate diastolic dysfunction
(B). The 2-dimensional maximal left atrial (LA) volume was determined by a biplane modified Simpson’s method based on the apical 2- and 4-chamber
views, and each LA volume was indexed by body surface area. Late diastolic tissue velocity (A ) was obtained by tissue Doppler measurements at the septal
mitral annulus. LAVi/A was finally calculated in all subjects.
Clin. Cardiol. 34, 2, 124–130 (2011)
H.- J. Park et al: LAVi/A as a new echo index to predict clinical outcomes
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
125
BNP Assay
Blood samples were collected in sterile tubes (EDTA) on the
same day of echocardiography. In all patients, plasma BNP
levels were measured by chemiluminescence immunoassay
(Bayer Diagnostics, Tarrytown, NY).12
Clinical Outcomes
Participants were followed for a median of 31.9 months
(range, 0.3 to 45.7 months) and were monitored on a regular
basis. The primary outcome in our study was the composite
of cardiac death and/or rehospitalization for CHF, which
was defined according to the Framingham critera.13
Statistical Analysis
All data are presented as mean ± standard deviation for
continuous variables and as frequency percentages for
categorical variables. Group comparisons were performed
using Student t and analysis of variance tests for continuous
variables and χ2 for frequency variables. Using receiveroperator characteristic curve analysis, we acquired the areas
under the curves (AUC) of BNP, E/E , LAVi, and LAVi/A
for the detection of ADD and then compared them by the
method of Hanley and McNeil.14
We divided all patients into 2 groups according to the best
cutoff value of LAVi/A and then compared the incidence
of clinical outcomes between them using the KaplanMeier survival curve. We also performed Cox proportional
hazards uni- and multivariate analyses to acquire the
odds ratios of prespecified risk factors, including BNP
≥ 200 pg/mL, E/E ≥15, LAVi ≥34 mL/m2 , and the best
cutoff value of LAVi/A for the detection of ADD. Statistical
analyses were performed with SPSS version 15.0 (SPSS Inc.,
Chicago, IL). For all analyses, P < 0.05 was considered
significant in identifying independent predictors of clinical
outcomes.
Results
Baseline Characteristics
Table 1 reports the baseline characteristics of 395 enrolled
patients. Among them, 174 (44.1%) patients had heart failure symptom with NYHA class III or IV. During the
admission periods, 93 (23.5%) patients received intravenous diuretics, 33 (8.4%) patients received intravenous
inotropes, and 15 (3.8%) patients received mechanical
ventilation.
Based on conventional diastolic function grading system,
the patients were divided into the following groups:
normal (n = 21, 5.3%), impaired relaxation (n = 291, 73.7%),
pseudonormal (n = 53, 13.4%), and restrictive physiology
(reversible and irreversible) (n = 30, 7.6%). As diastolic
function grade worsened, LV ejection fraction (LVEF)
gradually decreased, and LV mass, E/E , and LAVi gradually
increased. LAVi/A was similar between the normal and
impaired relaxation group, but it gradually increased in
patients with pseudonormal and restrictive physiology.
Plasma level of BNP also increased gradually according
to the diastolic function grade (Table 2).
126
Clin. Cardiol. 34, 2, 124–130 (2011)
H.- J. Park et al: LAVi/A as a new echo index to predict clinical outcomes
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
Table 1. Baseline Patient Characteristics (N = 395)
Clinical Variables
Age, y
63.0 ± 13.2
Male gender, n (%)
219 (55.4)
Body mass index, Kg/m2
24.4 ± 4.2
Body surface area, m2
1.67 ± 0.19
Hypertension, n (%)
180 (45.6)
Diabetes mellitus, n (%)
101 (25.6)
Hyperlipidemia, n (%)
74 (18.7)
Smoking, n (%)
70 (17.7)
Prior congestive heart failure (%)
42 (10.6)
Prior myocardial infarction, n (%)
56 (14.2)
Prior percutaneous coronary intervention, n (%)
107 (27.1)
Functional status of dyspnea
NYHA class
II
221 (55.9)
III
81 (20.5)
IV
93 (23.5)
SBP <90 mm Hg, n (%)
14 (3.5)
Heart rate ≥100 bpm, n (%)
38 (9.6)
Pulmonary edema or pleural effusion
59 (14.9)
Use of intravenous diuretics, n (%)
93 (23.5)
Use of intravenous inotropics, n (%)
33 (8.4)
Use of mechanical ventilator, n (%)
15 (3.8)
Laboratory findings
Hemoglobin, g/L
13.0 ± 2.0
Creatinine, mg/dL
1.02 ± 0.33
eGFR, mL/min
68.8 ± 27.7
Medication
ACE/ARB
193 (48.9)
Beta blocker
185 (46.8)
Calcium channel blocker
133 (33.7)
Diuretics
138 (34.9)
Abbreviations: ACE/ARB, angiotensin converting enzyme inhibitor/
angiotensin receptor blocker; bpm, beats per minute; eGFR, estimated
glomerular filtration rate by Cockcroft-Gault equation; NYHA, New York
Heart Association; SBP, systolic blood pressure.
LAVi/A As a New Echo Index to Identify Advanced Diastolic
Dysfunction
The AUC of LAVi/A for the entire study population was
comparable to that of BNP (0.94 vs 0.93, P = 0.845) and
Table 2. Comparison of Echocardiographic Variables and Plasma BNP Level According to Diastolic Dysfunction Grade
Diastolic Dysfunction Grade
Grade 0
Grade I
Grade II
Grade III–IV
Normal (n = 21)
Impaired Relaxation (n = 291)
Pseudonormal (n = 53)
Restrictive (n = 30)
LVEF (%)
63 ± 6
60 ± 10
LVMi (g/m2 )
90 ± 19
LAVi (mL/m2 )
14a
33 ± 13b
106 ± 30
134 ± 32c
155 ± 60d
22 ± 7
27 ± 12
50 ± 21c
50 ± 17c
Mitral E (cm/s)
73 ± 16
60 ± 17a
94 ± 28c
106 ± 23d
Mitral A (cm/s)
54 ± 15
79 ± 19c
60 ± 21
43 ± 16a
188 ± 32
240 ± 78c
154 ± 40a
118 ± 39b
PV, S (cm/s)
51 ± 13
58 ± 16
40 ± 15a
36 ± 15a
PV, D (cm/s)
45 ± 13
40 ± 10
57 ± 22c
68 ± 21d
PV, AR (cm/s)
25 ± 4
31 ± 21c
26 ± 11
26 ± 11
(cm/s)
8.7 ± 1.3
E (cm/s)
A (cm/s)
DT (msec)
S
PASP, (mm Hg)
43 ±
8.3 ± 1.8
6.1 ±
2.0a
4.9 ± 1.2b
11.3 ± 2.6
6.8 ± 1.9a
5.5 ± 1.9b
5.1 ± 1.7b
9.4 ± 1.6
10.7 ± 2.1c
7.7 ± 2.6a
5.1 ± 1.3b
25.9 ± 6.8
30.1 ± 8.7
44.1 ± 14.6c
50.3 ± 28.1c
Mitral E/E
6.7 ± 1.9
9.4 ± 4.2c
19.3 ± 9.3d
23.3 ± 10.5e
LAVi/A
2.4 ± 0.8
2.7 ± 1.6
7.2 ± 3.5c
10.6 ± 5.0d
BNP, pg/mL
57 ± 82
123 ± 336
1050 ± 1135c
1217 ± 1168c
Abbreviations: A, transmitral late diastolic velocity; A , late diastolic mitral annular velocity; AR, pulmonary venous atrial reversal flow; BNP, B type
natriuretic peptide; DT, deceleration time; E, transmitral early diastolic velocity; E , early diastolic mitral annular velocity; E/E , early diastolic transmitral
velocity to early diastolic mitral annular velocity; LAVi, left atrial volume index; LAVi/A , left atrial volume index over late diastolic mitral annular velocity;
LVEF, left ventricular ejection fraction; LVMi, left ventricular mass index; PV, D, pulmonary venous diastolic forward flow; PV, S, pulmonary venous peak
systolic forward flow; PV, S , peak systolic mitral annular velocity; PASP, pulmonary artery systolic pressure.
a, b Post-hoc analysis between the groups (P < 0.05, decreased values in comparison with Grade O)
c,d,e
Post-hoc analysis between the groups (P < 0.05, increased values in comparison with Grade O).
mitral E/E (0.94 vs 0.93, P = 0.614) and higher than that of
LAVi (0.94 vs 0.87; P = 0.014). These findings were largely
attributed to the difference of AUCs between LAVi/A and
LAVi in patients with LVEF <50% (0.89 vs 0.80; P = 0.017).
A LAVi/A of 4.0 was the best optimal cut-off value for
the determination of ADD, with a sensitivity of 89% and
specificity of 86%. In subgroup analysis of patients presenting
with 8 ≤ E/E <15, the AUC of LAVi/A to identify ADD
was similar to that of BNP (0.87 vs 0.88, P = 0.758)
and numerically higher than that of E/E (0.87 vs 0.80;
P = 0.258) and LAVi (0.87 vs 0.83; P = 0.512), although
this difference was statistically insignificant (Figure 2).
LAVi/A As a Predictor of Clinical Outcomes
During a median follow-up of 31.9 months (range, 0.3 to
45.7 months), 39/395 (9.9%) patients experienced cardiac
death (n = 10) or rehospitalization for CHF (n = 29). The
event rates of each cardiac death and rehospitalization
of CHF were higher in the group with LAVi/A ≥4.0
than the group with LAVi/A <4.0 (6/120 [5.0%] vs 4/275
[1.5%], P < 0.001; 24/120 [20.0%] vs 5/275 [1.8%], P <
0.001, respectively). Event-free survival curves also showed
a greater risk of adverse outcomes in the group of
LAVi/A ≥4.0 (log-rank test; P < 0.001, Figure 3). In Cox
proportional hazards multivariate analysis, LAVi/A ≥4.0
was an independent predictor of primary composite outcome
(odds ratio, 3.245; 95% confidence interval, 1.386–7.598;
P = 0.007) (Table 3).
Discussion
The current study shows that LAVi/A is a useful new
echo index to discriminate ADD in dyspneic patients with
a wide range of LVEF. LAVi/A has the additional benefit
in the assessment of the gray zone diastolic dysfunction
with 8 ≤ E/E <15. LAVi/A ≥4.0 is an independent
echocardiographic predictor of clinical outcomes.
E/E is a noninvasive surrogate index to estimate LV
filling pressure. Nagueh et al4 first demonstrated that E/E
correlated well (r = 0.87, P < 0.001) with PCWP using
the lateral mitral annulus for the measurement of E .
Ommen et al5 demonstrated that E/E (using the mitral
septal annulus) had a reasonable correlation (r = 0.64,
P < 0.001) with mean LV diastolic pressure in patients
referred for left heart catheterization. Some authors showed
Clin. Cardiol. 34, 2, 124–130 (2011)
H.- J. Park et al: LAVi/A as a new echo index to predict clinical outcomes
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
127
Figure 2. Receiver-operator characteristic curves for B-type natriuretic peptide (BNP), E/E , LAVi, and LAVi/A for the prediction of advanced diastolic
dysfunction. ∗ Statistically significant difference of area under the curve (AUC) compared to LAVi (P < 0.05).
its ability to predict future cardiovascular event and
mortality. Liang et al15 demonstrated that E/E and LAVi
were the best independent predictors of future heart failure
and provide prognostic information incremental to the
clinical history and LVEF.
With increasing acceptance of mitral E/E ratio as a
surrogate measure of diastolic function and a reliable
estimate of intracardiac filling pressure, LAVi/A provides
an important refinement to the clinical interpretation of
mitral E/E from a different view point of LV compliance. LV
compliance is an important factor affecting the contribution
of LA to diastolic performance, which maximizes LV filling
and protects the lungs from elevated LV end-diastolic
pressure.16,17 In patients with decreased LV compliance,
LA contribution to diastolic performance may decrease
and LA volume may increase due to elevated LV filling
pressure.9
128
Clin. Cardiol. 34, 2, 124–130 (2011)
H.- J. Park et al: LAVi/A as a new echo index to predict clinical outcomes
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
In the current study, LAVi/A , as a new echo index, has
several advantages over E/E and LAVi for the assessment
of diastolic dysfunction. First, LAVi/A may be potentially
useful in the diagnosis of chronic diastolic dysfunction
compared with E/E , which represents an acute stage of
elevated LV filling pressure.18 Our study demonstrate that a
LAVi/A value ≥ 4.0 is an independent predictor of primary
composite outcome (cardiac death and rehospitalization
for CHF), but E/E do not perform as well in predicting
these outcomes. Second, LAVi/A is a better index to
identify ADD among patients with 8 ≤ E/E <15. The
patient population with 8 ≤ E/E <15 is a gray zone that is
difficult to define and accurately determine clinical status.18
Based on our data, the AUC of LAVi/A is also higher
than that of E/E and LAVi in the subgroup analysis.
Third, LAVi/A is thought to be less influenced by age
as compared to E/E and LAVi.19 – 21 This characteristic
Table 3. Odd Ratios of Primary Composite Outcome (Cardiac Death and Re-Hospitalization for CHF) in 395 Patients With Dyspnea According to Cox Proportion
Hazard Analysis (Forward Conditional Method)
Univariate Analysis
Multivariate Analysis
Variables
OR
95% CI
P
OR
95% CI
P
Age ≥65 y
4.203
1.932−9.145
<0.001
—
—
—
Male gender
0.488
0.256−0.931
0.029
—
—
—
BMI ≥25 g/m2
0.526
0.250−1.107
0.091
Hb <12 g/dL
6.400
3.287−12.459
<0.001
2.841
1.352−5.969
0.006
eGFR <60 ml/min
8.665
3.823−19.639
<0.001
2.842
1.146−7.045
0.024
BNP ≥200 pg/mL
10.487
4.969−23.681
<0.001
3.108
1.214−7.954
0.018
LVEF <50%
3.050
1.627−5.717
0.001
—
—
—
PASP ≥40 mm Hg
5.603
2.972−10.562
<0.001
—
—
—
LAVi ≥34 mL/m
6.693
3.176−14.105
0.001
—
—
—
Mitral E/E ≥15
6.595
3.479−12.499
<0.001
—
—
—
LAVi/A ≥4
8.965
4.253−18.899
<0.001
2.658
1.104−6.401
0.029
2
Abbreviations: BMI, body mass index; CI, confidence interval; E/E , early diastolic transmitral velocity to early diastolic mitral annular velocity; eGFR,
estimated glomerular filtration rate by Cockcroft-Gault equation; Hb, hemoglobin; LAVi, left atrial volume index; LAVi/A , left atrial volume index over late
diastolic mitral annular velocity; LVEF, left ventricular ejection fraction; OR, odds ratio; PASP, pulmonary artery systolic pressure.
Unfortunately, we do not have invasive hemodynamic
data, such as PCWP, to correlate with LAVi/A . As
mentioned above, invasive measurement of LV filling
pressure with the cardiac catheterization would be helpful to
confirm the utility of LAVi/A for the prediction of elevated
LV filling pressure, although BNP and E/E are well
established as noninvasive methods of estimating LV filling
pressures. Because A can be measured only in patients
with normal sinus rhythm, it difficult to use this new index
in patients with atrial fibrillation or flutter. Furthermore,
our sample size and number of events are relatively small,
increasing the possibility of error.
Conclusion
As a unique echo index, LAVi/A is a useful parameter
to identify ADD and predict clinical outcomes in patients
with dyspnea. The clinical significance of this index needs
to be verified in a larger group of patients with longer
follow-up.
Figure 3. Kaplan-Meier and log-rank comparisons of the incidence of
cardiac death and/or rehospitalization for congestive heart failure
according to the LAVi/A cutoff value.
may be due to the compensatory role of A to LA volume
enlargement seen with the aging process, and may be
helpful in assessing diastolic dysfunction, especially in
elderly patients. Finally, LAVi/A is superior to LAVi in the
identification of ADD, especially in patients with decreased
LV systolic dysfunction. Our previous study showed that
LAVi had no statistical difference between groups with mild
and advanced diastolic dysfunction in patients with LVEF
<50%.22 LAVi/A may overcome this limitation by virtue of
adding LA contractile function to LA volume.
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Clin. Cardiol. 34, 2, 124–130 (2011)
H.- J. Park et al: LAVi/A as a new echo index to predict clinical outcomes
Published online in Wiley Online Library (wileyonlinelibrary.com)
DOI:10.1002/clc.20850  2011 Wiley Periodicals, Inc.
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