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pISSN 1975-4612/ eISSN 2005-9655

Copyright 2009 Korean Society of Echocardiography

DOI: 10.4250/jcu.2009.17.4.127

ORIGINAL ARTICLE

www.kse-jcu.org

J Cardiovasc Ultrasound 2009;17(4):127-134

Comparison of Left Ventricular

Hypertrophy, Fibrosis and Dysfunction
According to Various Disease Mechanisms
such as Hypertension, Diabetes Mellitus
and Chronic Renal Failure
Yoon-Seok Koh, MD, Hae-Ok Jung, MD, Mahn-Won Park, MD, Joo-Yeoul Baek, MD,
Sung-Gyu Yoon, MD, Pum-Joon Kim, MD, Sang-Hyun Ihm, MD, Kiyuk Chang, MD,
Yong-Seog Oh, MD, Ho-Joong Youn, MD, Sang Hong Baek, MD, Wook-Sung Chung, MD,
Ki-Bae Seung, MD and Jae-Hyung Kim, MD
Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of
Korea, Seoul, Korea

Background: Left ventricular hypertrophy (LVH) has been known as an important predictor of prognosis of cardiovascular
disease. Carboxy-terminal propeptide of procollagen type I (PIP) is related with myocardial fibrosis. We sought to analyze the
differences in the characteristics of LVH, myocardial fibrosis, and LV functions among hypertension (HBP), diabetes mellitus
(DM) and chronic renal failure (CRF).
Methods: We enrolled consecutive patients with LVH. Patients were grouped as HBP (n=50), DM (n=41), CRF (n=31).
Age and sex-matched normal control was also enrolled (n=32). Echocardiography and blood sampling for serum PIP level
measuring was performedin all participants.
Results: There were no differences in baseline characteristics except systolic blood pressure among four groups. In three
patients groups, their LV mass indices were significantly increased than control. Serum PIP level in CRF was much higher
than others (CRF 1505.5 vs. HBP 868.7 vs. DM 687.5 vs. control 826.4, p<0.0001). LV diastolic and systolic function
evaluated by E, E/E, S and midwall fractional shortening was significantly decreased in three patients groups. However,
LAVi was significantly elevated and LV ejection fraction was significantly decreased in CRF compared to others. In correlation analysis, indices of diastolic function were weakly, but statistically correlated with PIP (E: r=0.234, p=0.006; LAVi:
r=0.231, p=0.006).
Conclusion: In CRF, LV function was more deteriorated and serum PIP was more elevated when compared to HBP or DM.
Therefore, myocardial fibrosis may play an important role to LV dysfunction as well as LV hypertrophy in CRF in some degree.

KEY WORDS: Left ventricular hypertrophyCarboxy-terminal propeptide of procollagen type IFibrosis.

Introduction

Essential hypertension (HBP), type 2 diabetes mellitus

(DM) and chronic renal failure (CRF) induce left ventricular
hypertrophy (LVH), and patients with LVH is significantly

associated with higher occurrence of cardiovascular death

compared with normal population.1-3) However, the common
echocardiographic findings of LVH without combined severe
cardiovascular complications are merely expressed diastolic

Received: October 21, 2009 Revised: November 30, 2009 Accepted: November 30, 2009
Address for Correspondence: Hae-Ok Jung, Division of Cardiology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, 505
Banpo-dong, Seocho-gu, Seoul 137-404, Korea Tel: +82-2-2258-1128, Fax: 82-2-2258-1138, E-mail: [email protected]

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Journal of Cardiovascular Ultrasound 17 | December 2009

dysfunction, grade I (impaired relaxation abnormality) and

normal systolic function in patients with above three diseases
in general.4) Also in clinical situation, the stage of only LVH
in three diseases is not regarded as abnormal cardiac function,
so active diagnostic process and treatment has not been applied.
Nevertheless many clinical researches have shown that LVH
itself is an important prognostic predictor for occurrence of
cardiovascular diseases and cardiovascular mortality.5)6)
In HBP, it has been explained that the mechanism of LVH
is due to hypertrophy of cardiomyocyte caused by the adaptation of increased afterload, but recent studies give an account
that abnormal fibrosis in myocardial interstitium plays an
important role in LVH.1)7)8) Furthermore, in DM and CRF
it has been reported that the increased fibrosis in myocardial
interstitium affect LVH.3)4) Fibrosis in myocardial interstitium induces the diastolic dysfunction due to decreased the
elasticity of myocardium and results in systolic dysfunction.
The histopathological proof by direct biopsy of myocardium
is the best method in the existence of myocardial fibrosis, but
in real world it is impossible to perform myocardial biopsy in
all patients. On the other hand, it has been known that the
plasma level of carboxy-terminal propeptide of procollagen
type I (PIP) reflecting the synthesis of type I collagen is well
correlated with fibrosis in myocardial interstitium.9-11) So the
degree of myocardial fibrosis can be estimated by the measurement of the serum PIP level.
As above, abnormally increased myocardial fibrosis plays
an important role in the mechanism of LVH, hinder the
elasticity of myocardium and systolic function and then
decrease blood supply resulting in inducing cardiac dysfunction in all three diseases.
The aims of present study were 1) to analyze the differences in the characteristics of LV hypertrophy, myocardial
fibrosis, and LV systolic and diastolic function between HBP,
DM and CRF, 2) to search the relation between myocardial
fibrosis and LV function in patients with LVH.
Materials and Methods
Study populations

We enrolled consecutive patients with LVH, who underwent transthoracic echocardiography from June 2006 to
October 2008 at Kangnam St. Marys Hospital. LVH was
defined as left ventricular mass index >125 g/m2 regardless
of gender measured by 2-dimension guided M-mode echocardiography. LV mass was calculated using the formula of
Devereux and indexed to body surface area. These patients
were evaluated by chart review and history taking, and finally
50 patients with essential hypertension (HBP group), 41
patients with type 2 diabetes mellitus (DM group), and 31
patients with chronic renal failure (CRF group) were includ128

ed and classified for the study. Age and sex-matched 32

normal persons were also enrolled as control. Inclusion criteria
were as below: 1) HBP: patients who had systolic blood
pressure 140 mmHg or diastolic blood pressure 90 mmHg
at consecutive 2 or more visits, or who took anti-hypertensive medications already without history of DM or CRF, and
their fasting blood sugar and creatinine were within normal
limit; 2) DM: patients who had fasting blood glucose 126
mg/dL two times or more or who took hypoglycemic drugs
already without history of HBP or CRF, and their creatinine
was within normal limit; 3) CRF: patients who have creatinine clearance (CCr) <15 mL/min/1.73 m2 by CockcroftGault equation during recent 3 months or longer, or already
treated by dialysis. Exclusion criteria were as below: 1) LV
ejection fraction <45%; 2) myocardial infarction, ischemic
cardiomyopathy or dilated cardiomyopathy; 3) pulmonary
hypertension or right heart failure; 4) moderate or severe
pericardial effusion; 5) atrial arrhythmia including atrial
fibrillation; 6) moderate or severe valvular heart disease; 7)
history of valve replacement, open chest surgery or permanent pacemaker insertion; 8) rheumatologic disease; 9) hematologic or oncologic disease; 10) hypertropic cardiomyopathy;
11) infiltrative cardiomyopathy such as amyloidosis; 12)
current use of steroid. The institutional medical ethics committee approved the study protocol. All participants gave
informed consent to undergo the study.
Echocardiogarphy

Transthoracic echocardiography was performed by using

commercially available ultrasound equipments (Acuson Sequoia 512, Siemens Medical, Mountain View, CA, USA;
Vivid-7, GE Medical Systems, Milwaukee, WI, USA) for
the obtaining 2-dimensional, M-mode, color Doppler imaging
and tissue Doppler imaging according to standardized
method by American Society of Echocardiography.12-14) All
echo indices were calculated by the mean of two measurements. In present study, we measured cardiac echo indices as
below: 1) interventricular septum and posterior wall thickness
at end-diastole; 2) LV dimension at end-diastole and endsystole; 3) left atrial (LA) dimension at end-systole; 4) LV
volume at end-diastole and end-systole; 5) LA volume at
end-systole; 6) left ventricular mass index (LVMi); 7) relative
wall thickness; 8) transmitral inflow Doppler: early diastolic
wave (E), late diastolic wave (A), duration of A (A dur) and
decelerating time of E (DT); 9) tissue velocity on septal mitral
annulus: systolic (S), early diastolic (E), late diastolic (A)
velocity; 10) pulmonary venous flow Doppler: duration of
reverse A wave (Ar dur); 11) indices of diastolic function: E,
E/E, DT, Ar dur-A dur, left atrial volume index (LAVi); 12)
indices of systolic function: LV ejection fraction (LVEF), S,
midwall fractional shortening (FS midwall).

Left Ventricular Hypertrophy and Fibrosis | Yoon-Seok Koh, et al.

procollagen type I.9-11)15)

Measurement of serum PIP

Venous blood was sampled with minimal stimulus in all

participants for the measuring of serum PIP level in all participants. And then serum was extracted by centrifuge (2,000
G, 10 minutes) and kept at -70C refrigerator until quantitative analysis. Level of PIP in serum was quantified by precoated type I step sandwich enzyme immunoassay (measurement range: 10-640 ng/mL, detection sensitivity: 10 ng/mL;
Takara bio, Shiga, Japan) using monoclonal anti-human

Statistical analysis

Continuous data are expressed as meanSD. Data of 4

groups were compared by ANOVA and post-hoc analysis
(Turkey-b). The correlation of plasma level of PICP and
diastolic or systolic functional echo indices was analyzed by
Pearson correlation. For all analyses, a two-sided p<0.05 was
considered statistically significant. Statistical analysis was

Table 1. Baseline characteristics of study population

Clinical characteristics
Age (yr)
Sex (male, %)
Height (cm)
Weight (Kg)
BSA (/m2)
Systolic BP
Diastolic BP
BMI (kg/m2)
Drug CCB (%)
BB (%)
ACEi (%)
ARB (%)

Control (n=32)
59.212.0
58.8
169.88.7
65.217.2
1.730.21
126.18.8
80.19.9
23.13.8
0
0
0
0

HBP (n=50)
61.212.0
56.9
168.616.1
66.413.4
1.720.2
137.325.1
82.214.1
26.914.6
50.0*
32.0*
24.0*
48.0*

DM (n=41)
63.49.21
63.7
173.613.6
75.710.9
1.790.17
122.517.3
75.410.3
23.93.2
0
3.5
15.3
1.7

CRF (n=31)
59.614.7
64.3
170.69.1
72.711.2
1.780.18
138.723.9
78.712.6
24.74.1
31.9*
42.6*
53.8*
40.4*

p-value
Ns
Ns
Ns
Ns
Ns
<0.05
Ns
Ns
<0.05
<0.05
<0.05
<0.05

*p<0.05 versus control and diabetes. Ns: non-specific, HBP: hypertension, DM: diabetes, CRF: chronic renal failure, BSA: body surface area, BP: blood
pressure, BMI: body mass index, CCB: calcium channel blocker, BB: beta blocker, ACEi: angiotensin converting enzyme inhibitor, ARB: angiotensin
receptor blocker
Table 2. M-mode and 2-dimentional echocardiographic indices

Echocardiographic indices
Diastolic LVID (mm)
Systolic LVID (mm)
IVS thickness (mm)
PW thickness (mm)
LV mass index (g/m2)
RWT (%)
LA dimension (mm)
LA volume index (mL/m2)
LVEF (%)
FSmidwall (%)

Control (n=32)
48.45.7
29.25.5*
9.82.6
9.62.6
95.032.1
0.410.13
35.24.4*
24.19.0*
64.26.2*
21.46.9

HBP (n=50)
49.15.1
29.55.0*
12.91.1
12.71.2
149.925.3
0.530.08
36.65.2*
30.911.3*
64.76.1*
16.73.7

DM (n=41)
50.37.3
31.78.9*
13.52.0
13.52.0
152.759.2
0.550.10
37.54.7*
30.312.9*
60.88.0*
15.33.6

CRF (n=31)
52.17.6
35.69.1
13.32.5
13.32.5
168.373.3
0.530.11
41.06.3
45.216.9
56.010.8
14.63.9

p-value
0.101
0.001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

*p0.001 versus chronic renal failure, p<0.0001 versus control. LVID: left ventricular internal dimension, IVS: interventricular septum, PW: posterior wall,
LV: left ventricle, RWT: relative wall thickness, LA: left atrium, LVEF: left ventricular ejection fraction, FS: fractional shortening
Table 3. Transmitral inflow Doppler and tissue Doppler indices by echocardiography

Indices
E
DT
S
E
A
E/E
Ar dur-A dur

Control (n=32)
60.413.9*
199.070.2
8.61.8
8.43.0
8.62.4
7.93.1
20.914.7

HBP (n=50)
58.416.3*
265.778.6
7.61.6
5.51.6
7.92.4
11.34.5
25.122.1

DM (n=41)
57.015.2*
231.160.3
7.41.7
5.11.6
6.72.4
12.54.5
27.820.6

CRF (n=31)
75.230.4
199.960.1
7.31.8
5.11.0
6.32.4
12.57.3
29.819.8

p-value
<0.0001
<0.0001
0.016
<0.0001
<0.0001
<0.0001
Ns

*p<0.0001 versus chronic renal failure, p<0.05 versus control. Ns: non-specific, DT: decelerating time, dur: duration

129

Journal of Cardiovascular Ultrasound 17 | December 2009

performed with SPSS (version 11.5 for window, SPSS, Inc.,

Chicago, IL, USA).
Results
Clinical baseline characteristics of study
population

phy were manifested in Table 2 and Table 3. In CRF group,

end-systolic LV internal dimension, LA dimension, LAVi
were larger than other three groups (p=0.001, p<0.0001,
p<0.0001, respectively) (Fig. 1). Interventricular septum, LV
posterior wall, relative wall thickness and LV mass index of 3
disease groups (HBP, DM, CRF) were significantly larger
than control (p<0.0001, all). LV systolic function evaluated

Table 1 shows clinical baseline characteristics of four groups.

There was no significant difference in age, ratio of male
gender, body surface area and body mass index among four
groups. In HBP and CRF groups, systolic blood pressure
(SBP) was higher than in DM and normal groups (HBP
137.3 mmHg vs. DM 122.5 mmHg vs. CRF 138.7 mmHg
vs. normal 126.1 mmHg, p<0.05), but in case of diastolic
blood pressure (DBP) did not show significant differences
among four groups. Antihypertensive agents were prescribed
optimally in all patients with HBP and CRF. In DM group,
blood sugar level was well controlled by oral hyperglycemic
agent.
Cardiac indices by echocardiography

The results of 2-dimensional and M-mode echocardiogra-

Fig. 1. Left ventricular mass index (LVMi) by M-mode among four

groups. HBP: hypertension, DM: diabetes, CRF: chronic renal failure.

Fig. 2. Indices of systolic function among four group. A: Left ventricular ejection fraction (LVEF) among four groups: in CRF groups, LVEF was
statistically decreased. B: Fractional shortening midwall (FSmidwall) among four groups: in HBP, DM and CRF group, FSmidwall was significantly
decreased. C: S among four groups: in HBP, DM and CRF group, S was significantly decreased. CRF: chronic renal failure, HBP: hypertension, DM:
diabetes.

Fig. 3. Indices of diastolic function among four group. A: Left atiral volume index (LAVi) among four groups: in CRF group, LAVi was significantly
increased. B: E among four groups: in HBP, DM and CRF group, E was significantly decreased. C: E/E among four groups: in HBP, DM and CRF
group, E/E was significantly increased. CRF: chronic renal failure, HBP: hypertension, DM: diabetes.

130

Left Ventricular Hypertrophy and Fibrosis | Yoon-Seok Koh, et al.

by systolic mitral annular tissue velocity (S) and midwall fractional shortening (FSmidwall) were significantly decreased in
3 disease groups than control. However, there were no differences in S and FSmidwall between 3 disease groups. LV
ejection fraction, a load dependent marker of LV contraction,
was significantly decreased in CRF compared with HBP,
DM and control (Fig. 2). LV diastolic function evaluated by
E and E/E was significantly decreased in 3 disease groups
than control. However, there were no differences in E and
E/E between 3 disease groups. LAVi, an index of chronic
diastolic load, was significantly elevated in CRF compared to
others (Fig. 3). Ar dur-A dur, an index of LV diastolic compliance, was not different among 4 groups.

The correlation of serum PIP and the index of LV systolic

function such as LVEF and S are expressed in Fig. 5. There
was no significant correlation between serum PIP and LV
systolic function. Fig. 6 shows the correlation between serum
PIP and the index of LV diastolic function such as LAVi, E
and E/E. There were weakly positive correlations between
serum PIP and E or LAVi (r=0.234, p=0.006; r=0.231, p=
0.006, respectively). But there was no significant correlation
between serum PIP and E/E. In the analysis of each group,
only E was statistically correlated with PIP level in patients
with DM and CRF (Table 4).

The serum level of PIP

Discussion

Fig. 4 shows the serum level of PIP among 4 groups. In

CRF group, the serum PIP was significantly higher than
other 3 groups (CRF 1505.5 ng/mL vs. HBP 868.7 ng/mL
vs. DM 687.5 ng/mL vs. normal 826.4 ng/mL, p<0.0001).
However, when compared all patients with LVH with control,
there was no significant difference in serum PIP.

In present study, the shape of LVH in HBP, DM and CRF

was all concentric, degree of LVH was not different each other.
In the results of this study, decreased LV diastolic function
was noted in all 3 disease groups. Especially, LA volume
index, a result of chronic load of diastolic dysfunction was
larger only in CRF. It means that CRF has worst diastolic
function among 3 disease groups. LV systolic function

Correlation between the serum PIP and

systolic function or diastolic function

B
Fig. 4. A: Serum level of Carboxy-terminal propeptide of procollagen
type I (PIP) among four groups: in CRF group, serum PIP level was
significantly higher than other three groups. B: Serum level of PIP
between patients with LVH and normal group. HBP: hypertension, DM:
diabetes, CRF: chronic renal failure.

Fig. 5. Correlation between Serum Carboxy-terminal propeptide of

procollagen type I (PIP) level and index of systolic function. A:
Correlation between serum PIP level and LVEF. B: Correlation between
serum PIP level and S.

131

Journal of Cardiovascular Ultrasound 17 | December 2009

C
Fig. 6. Correlation between serum Carboxy-terminal propeptide of
procollagen type I (PIP) level and index of diastolic function. A:
Correlation between serum PIP level and LAVi. B: Correlation between
serum PIP level and E. C: Correlation between serum PIP level and
E/E.

represented as S and FSmidwall was markedly decreased in

3 disease groups. In addition, LVEF was significantly decreased in CRF group than other 3 groups. It means that
CRF have worst systolic function among 3 disease groups.
The serum PIP which was known to reflect the state of
myocardial fibrosis well9-11) was much higher in CRF group
in spite of optimal anti-hypertensive agents compared with
other three groups. It suggests that myocardial fibrosis may
be related to LV dysfunction as well as the mechanism of LVH
in CRF in some degree. In other words, myocardial fibrosis
may be more excessive and may induce diastolic and systolic
dysfunction in CRF although the degree of LVH in CRF is
similar to HBP or DM.
About the development of LVH, several mechanisms are
suggested. In HBP, arteriosclerosis of large arteries and
increased resistance of muscular arterioles induce elevated
afterload to heart and finally hypertrophy of cardiomyocytes
develops for the maintaining the tension of ventricular
wall.16) It has been so called Laplaces law. In case of DM,
non-enzymatic glycosylation plays a key role for LVH. It
provokes the changes of chemical composition of proteins in
cardiomyocytes and then the structure and function of cells
are changed. This process induces the obstacle of calcium
delivery, the suppression of myocardial systolic proteins and
the inhibition of the metabolism of fatty acid, so due to these
phenomena abnormal cardiomyocytes hypertrophy may
progresses.17)18) In another theory, advanced glycation endproduct (AGE) links with myocardial collagen and extracellular proteins, and then the combination products deposit
in tissue. These deposited combination product stimulate
tissue growth factor and transforming growth factor-beta1
(TGF-b1). Finally, this process induce cardiomyoctye hypertrophy and fibroblast hypertrophy resulting in myocardial
fibrosis.19)20) In CRF, it has been explained that the causes
of LVH are pressure overload due to HBP and volume overload
of retained intravascular fluid and anemia.3)21)22) As above, it
has been known that the mechanism of LVH is different
among three diseases, but recently it has been established
that myocardial fibrosis is common mechanism.1)7)8)17-20)23)
However, it has not been known in which disease the degree
of myocardial fibrosis is more excessive, the present study

Table 4. Correlation between Carboxy-terminal propeptide of procollagen type I (PIP) and variable echocardiographic indices according to groups

Variables
EF
S
E/E
E
LAVi

Normal
r
-0.216
0.086
-0.120
0.085
0.185

HBP
p-value
0.512
0.650
0.512
0.644
0.355

r
-0.019
-0.031
-0.039
0.185
0.065

DM
p-value
0.895
0.843
0.785
0.219
0.666

r: correlation coefficient. HBP: hypertension, DM: diabetes, CRF: chronic renal failure

132

r
0.081
0.035
-0.064
0.317
0.140

CRF
p-value
0.620
0.834
0.695
0.046
0.401

r
0.120
0.308
-0.073
0.419
-0.040

p-value
0.520
0.097
0.695
0.005
0.832

Left Ventricular Hypertrophy and Fibrosis | Yoon-Seok Koh, et al.

suggests that myocardial fibrosis in CRF may be more severe

than HBP or DM in view of increased serum PIP level. Also
serum PIP is known to be excreted not by kidney, but by
liver,11) and may reflect myocardial fibrosis in CRF regardless
of creatinine level.
Myocardial fibrosis is more prominent due to pressure overload than volume overload. Also myocardial fibrosis is associated with aging, ischemia, catecholamine, angiotensin II,
aldosterone, TGF and inflammatory cell and it has been suggested that inflammatory mediated substances such as
interleukin-6, monoctye chemoattractant protein-1 induce
inflammatory process and affect myocardial fibrosis.3)24)25) In
view of above mechanisms, severe inflammatory reaction
due to uremia may enhance severe myocardial fibrosis in
some degree. But, in a few articles, elevated PIP in patients
with CRF might be a biomarker of bone metabolism.26)27)
On the other hand, it was published that elevated PIP was
not correlated with classic bone turnover markers such as
intact parathyroid hormone, osteocalcin and alkaline phosphatase,27) and bone mineral density.28) In other words, it
should not be interpreted that elevated PIP level was due to
only bone turnover or only myocardial fibrosis. So elevated
PIP level in patients with CRF may be resulted from a few
causes such as myocardial fibrosis or bone metabolism.
However, in Pearson correlation, serum PIP level was not
directly correlated with the indices of systolic function such
as LVEF and S. The causes of these results may be the feature
of selected patients with preserved left ventricular systolic
function. In case of diastolic function, there was weakly
positive correlation between serum PIP level and the indices
of diastolic function such as LAVi or E but not E/E. Furthermore, in view of the analysis according to each group, only
E was statistically correlated with PIP level in patients with
DM and CRF. These results may be caused by the examination time, so to speak most patients are not diagnosed initially,
but already have been treated optimally according to disease.
These phenomena are also observed in other study.29) Also in
a few studies, LV mass, diastolic function and systolic function
were improved after optimal antihypertensive treatment in
patients with HBP,30)31) after kidney transplantation in patients
with dialysis.32) In other words, if echocardiographic examination and PIP level measuring was performed at diagnosis
as HBP, DM and CRF initially, there might be the potentiality that PIP level might be correlated with echocardiographic indices. In the present study, echocardiographic examination and blood sampling time was very various according
to each patient, so it might reflect these results.
In summary, LV systolic and diastolic function was more
deteriorated and serum PIP was more elevated in CRF. It
may suggest that myocardial fibrosis may play an important
role to LV dysfunction as well as LV hypertrophy in CRF in

some degree.
There are a few limitations in the present study. First, the
present study is not prospective random trial but cross-section
study, so patients who were newly diagnosed as HBP, DM or
CRF were not selected but have been treated optimally. Due
to these selections, serum PIP level was not differently in
patients with HBP, DM compared with normal population.
Second, the follow up measurements of echocardiography
and serum PIP level were not performed regularly, so the
improvement of cardiac function and serum PIP level was
not grasped. In future, the study that regular follow up measurement of echocardiography and serum PIP level is performed and the change of indices of variable echocardiographic
findings and serum PIP level are analyzed will need.
Acknowledgements
The study was supported by the industry and academy collaboratory
research fund 2006 of Korean Society of Echocardiography.
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