Serum syndecan-4 is a novel biomarker for patients with chronic heart failure.
ABSTRACT Syndecan-4 is a transmembrane heparan sulfate-carrying glycoprotein that mediates signal transduction pathways activated by growth factors and cell surface receptors, thereby modulating tissue regeneration, angiogenesis, and focal adhesion. The aim of the present study was to determine the clinical use of serum syndecan-4 concentration for diagnosis of heart failure.
Concentration of serum syndecan-4 and other biomarkers of heart failure was measured in 45 patients with heart failure and 21 healthy subjects. Clinical and echocardiographic parameters of cardiac function were recorded.
Serum syndecan-4 concentration significantly increased in proportion to the decrease in ejection fraction (r=-0.599, p<0.001) and increase in the left ventricular (LV) mass index (r=0.315, p<0.05). Serum syndecan-4 concentration was significantly correlated with LV geometrical parameters (i.e. LV mass index, LV end-diastolic volume, and LV dimension), while B-type natriuretic peptide (BNP) was significantly correlated with pressure-related parameters [i.e. early transmitral flow velocity/early diastolic velocity of the mitral valve annulus (E/e'), right ventricular systolic pressure, and left atrial volume index]. Syndecan-4 concentration did not significantly correlate with plasma BNP, transforming growth factor-1, matrix metalloproteinase-2, and tenascin-C concentrations. Serum syndecan-4 concentration could predict cardiac death and re-hospitalization due to heart failure (area under curve, 0.706, p<0.05).
Serum syndecan-4 concentration shows promise as a novel diagnostic and prognostic biomarker for heart failure. Since syndecan-4 correlated with LV geometrical rather than hemodynamic parameters, serum syndecan-4 may represent a biomarker of LV remodeling in the failing heart.
- SourceAvailable from: PubMed Central[Show abstract] [Hide abstract]
ABSTRACT: A human syndecan-4 genetic variant (rs1981429) has previously been associated with lean tissue mass and intra-abdominal fat, and SNP rs4599 with resting energy expenditure in healthy early pubertal children. These variations could thus cause overweight and hypothetically lead to hypertension. Their association with body mass index and blood pressure was therefore studied in a Finnish cohort of adults. The data was collected from the Tampere adult population cardiovascular risk study (TAMRISK). A total of 279 cases with hypertension and/or coronary artery disease (CAD), and 488 non-hypertensive healthy controls were selected from a Finnish periodic health examination 50-year-old cohort. Information was available also from their 45-year examination. DNA was extracted from buccal swabs and human syndecan-4 gene SNPs were analyzed using KASP genotyping. The SNP rs1981429 variant TT was significantly associated with hypertension, as compared to variants TG and GG at the age of 50 years (p=0.015). The variant TT was also associated with increased BMI at the ages of 45 and 50 years (p=0.008 and p=0.026, respectively). In addition, TT genotype associated with increased CAD prevalence (P=0.013). No significant associations between rs4599 variants and hypertension or BMI were found. In haplotype analysis the number of alleles T (rs1981429) / C (rs4599) was linearly associated with CAD prevalence; the highest prevalence (13%) was in haplotype TT / CC and lowest prevalence (1%) in haplotype GG / TT (p=0.01). Syndecan-4 polymorphisms were associated with essential hypertension, BMI, and CAD prevalence in the TAMRISK study.BMC Research Notes 11/2014; 7(1):815.
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ABSTRACT: In contrast to public perception, the morbidity and mortality and the resultant healthcare costs associated with chronic heart failure (HF) are increasing and arguably reaching epidemic proportions. Although basic research efforts have provided unique insights into fundamental processes that govern myocardial extracellular matrix (ECM) growth and function, the translation of these findings to improved diagnostics and therapeutics for HF has not been as forthcoming. The factors that contribute to this relative paucity of new clinical tools for HF are multifactorial but likely include the need to recognize and differentiate HF phenotypes and to couple the use of biomarkers and multimodality imaging in early translational research studies. Recognizing the classification scheme of HF with a reduced ejection fraction (EF) to that of HF with a preserved EF and incorporating unique and differential measurements of ECM remodeling to these specific disease processes are warranted. For example, profiling pathways of ECM degradation such as the matrix metalloproteinases in patients with ischemic heart disease and HF with a reduced EF can provide prognostic information in terms of risk of progression to HF. In patients with chronic hypertensive disease and HF with a preserved EF, plasma profiling indexes of ECM synthesis and turnover, as well as advances in ECM imaging, have been shown to provide diagnostic and prognostic use. In terms of therapeutics, strategies to stabilize the ECM in HF with a reduced EF hold potential, whereas in contradistinction, selective antifibrotic agents may hold promise for HF with a preserved EF. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT 00946231.Circulation Research 08/2013; 113(6):725-38. · 11.09 Impact Factor
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ABSTRACT: Heparan sulfate proteoglycans act as co-receptors for many chemokines and growth factors. The sulfation pattern of the heparan sulfate chains is a critical regulatory step affecting the binding of chemokines and growth factors. N-deacetylase-N-sulfotransferase1 (Ndst1) is one of the first enzymes to catalyze sulfation. Previously published work has shown that HSPGs alter tangent moduli and stiffness of tissues and cells. We hypothesized that loss of Ndst1 in smooth muscle would lead to significant changes in heparan sulfate modification and the elastic properties of arteries. In line with this hypothesis, the axial tangent modulus was significantly decreased in aorta from mice lacking Ndst1 in smooth muscle (SM22αcre(+)Ndst1(-/-), p < 0.05, n = 5). The decrease in axial tangent modulus was associated with a significant switch in myosin and actin types and isoforms expressed in aorta and isolated aortic vascular smooth muscle cells. In contrast, no changes were found in the compliance of smaller thoracodorsal arteries of SM22αcre(+)Ndst1(-/-) mice. In summary, the major findings of this study were that targeted ablation of Ndst1 in smooth muscle cells results in altered biomechanical properties of aorta and differential expression of myosin and actin types and isoforms.Molecular and Cellular Biochemistry 10/2013; 385(1-2). · 2.39 Impact Factor
Journal of Cardiology (2011) 57, 325—332
available at www.sciencedirect.com
journal homepage: www.elsevier.com/locate/jjcc
Serum syndecan-4 is a novel biomarker for patients
with chronic heart failure
Rieko Takahashi (MD)a, Kazuaki Negishi (MD)a, Atai Watanabe (MD, PhD)a,
Masashi Arai (MD, PhD)a,∗, Fumio Naganuma (MD, PhD)b,
Yoshiaki Ohyama (MD)a, Masahiko Kurabayashi (MD, PhD, FJCC)a
aDepartment of Medicine and Biological Science, Gunma University Graduate School of Medicine, 3-39-22 Showa-machi,
Maebashi, Gunma 371-8511, Japan
bDepartment of Cardiology, Tsurugaya Hospital, Gunma, Japan
Received 12 November 2010; received in revised form 24 January 2011; accepted 26 January 2011
Available online 11 March 2011
Background: Syndecan-4 is a transmembrane heparan sulfate-carrying glycoprotein that medi-
ates signal transduction pathways activated by growth factors and cell surface receptors,
thereby modulating tissue regeneration, angiogenesis, and focal adhesion. The aim of the
present study was to determine the clinical use of serum syndecan-4 concentration for diagnosis
of heart failure.
Methods: Concentration of serum syndecan-4 and other biomarkers of heart failure was mea-
sured in 45 patients with heart failure and 21 healthy subjects. Clinical and echocardiographic
parameters of cardiac function were recorded.
Results: Serum syndecan-4 concentration significantly increased in proportion to the decrease
in ejection fraction (r=−0.599, p<0.001) and increase in the left ventricular (LV) mass index
(r=0.315, p<0.05). Serum syndecan-4 concentration was significantly correlated with LV geo-
metrical parameters (i.e. LV mass index, LV end-diastolic volume, and LV dimension), while
B-type natriuretic peptide (BNP) was significantly correlated with pressure-related parame-
ters [i.e. early transmitral flow velocity/early diastolic velocity of the mitral valve annulus
(E/e?), right ventricular systolic pressure, and left atrial volume index]. Syndecan-4 concen-
tration did not significantly correlate with plasma BNP, transforming growth factor-1, matrix
metalloproteinase-2, and tenascin-C concentrations. Serum syndecan-4 concentration could
predict cardiac death and re-hospitalization due to heart failure (area under curve, 0.706,
∗Corresponding author. Tel.: +81 27 220 8142; fax: +81 27 220 8158.
E-mail address: email@example.com (M. Arai).
0914-5087/$ — see front matter © 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
326R. Takahashi et al.
Conclusion: Serum syndecan-4 concentration shows promise as a novel diagnostic and prognostic
biomarker for heart failure. Since syndecan-4 correlated with LV geometrical rather than hemo-
dynamic parameters, serum syndecan-4 may represent a biomarker of LV remodeling in the failing
© 2011 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Chronic heart failure results from myocardial degradation
and pathologic structural regeneration in a process known
as cardiac remodeling. This multistage and multicellular
repair process is mediated by a complex interplay between
growth factors and cytokines. Progressive and end-stage
heart failure is a culmination of this pathologic process.
Many biomarkers have been proposed to diagnose heart fail-
ure and predict prognosis of the patient. However, the type
of cardiac function that each biomarker represents remains
Various studies have demonstrated that extracellular
matrix (ECM) components, namely proteoglycans and fibrous
proteins such as collagen, play an essential role in car-
diac remodeling. Although the role of collagen in cardiac
hypertrophy and heart failure has already been well char-
acterized, comparatively little is known about the role of
proteoglycans. Proteoglycans bind to long-chain polysac-
charide glucosaminoglycans on the cell surface, and those
consisting of transmembrane core proteins carrying heparan
and chondroitin sulfate are called syndecans. Syndecans
are thought to mediate cardiac remodeling by transmit-
ting the cellular actions of a number of growth factors,
including fibroblast growth factor, vascular endothelial
growth factor, and transforming growth factor-beta (TGF-?)
Syndecan-4 (ryudocan) is the most extensively studied
isoform of the syndecan family. Syndecan-4 knockout mice
show delayed wound repair and impaired angiogenesis . In
the skeletal muscle of syndecan-4 knockout mice, satellite
cells cannot reconstitute damaged cells and cannot pro-
liferate and differentiate into myotubes, suggesting that
syndecan-4 also participates in muscle development and
regeneration . Furthermore, the plasma syndecan-4 level
is elevated in patients with acute myocardial infarction with
a peak at 2 weeks after infarction .
Although syndecan-4 plays a significant role in the car-
diovascular system, the role of syndecan-4 in heart failure
remains unclear. Thus, the present study investigated the
clinical use of serum syndecan-4 concentration as a rep-
resentative component of ECM in the diagnosis of heart
failure. The aims of the study were: (1) to determine which
echocardiographic parameters are represented by serum
syndecan-4 concentration; (2) to determine whether serum
syndecan-4 concentration predicts prognosis of patients
with heart failure; and (3) to determine the difference
between syndecan-4 as a potential biomarker for heart fail-
ure and those currently being used [i.e. B-type natriuretic
peptide (BNP), TGF-?1, matrix metalloproteinase-2 (MMP2),
and tenascin-C]. At present, BNP is considered the most
powerful predictor of cardiac death and re-hospitalization
for heart failure. TGF-?1 and MMP2 regulate ECM turnover,
and tenascin-C is another proteoglycan that reportedly
increases in the failing heart .
Materials and methods
A local ethics committee and internal review board
approved this study. All protocols conformed to the ethi-
cal guidelines of the 1975 Declaration of Helsinki. Written
informed consent was obtained from all patients.
This study enrolled 45 Japanese patients with chronic
heart failure (31 men and 14 women), age 30—97 years
(mean age 64.8±15.9 years), who were admitted to Gunma
University Hospital, Tomioka General Hospital, and Tsuru-
gaya Hospital between June 2006 and February 2007 for
the treatment of heart failure, in addition to 21 healthy
subjects (12 men and 9 women, and age 25—81 with mean
age 49.2±12.5 years). The main demographic and clinical
characteristics of the patients are summarized in Table 1.
The prevalence of idiopathic dilated cardiomyopathy, hyper-
trophic cardiomyopathy, ischemic cardiomyopathy, and
hypertensive cardiomyopathy was 22%, 13%, 20%, and 44%,
respectively. The present study excluded patients with
a history of neoplastic, hepatic, infectious, collagen, or
peripheral atherosclerotic diseases or patients who under-
went any surgical procedure in the preceding 6 months.
None of the patients had signs of infection and collagen
disease at the time of evaluation.
Patients were followed for 3 years and their clinical
outcomes were recorded. The endpoint of follow-up was
defined as cardiac death or re-hospitalization due to heart
failure. Cardiac death during the re-hospitalization was
counted as single event. Additionally, second or more re-
hospitalizations were not counted as additional events but
single event at the time of first re-hospitalization.
Blood sampling and measurement of syndecan-4
Plasma and serum samples were obtained from peripheral
venous blood. Whole blood was withdrawn from an ante-
cubital vein, placed in tubes containing sodium EDTA, and
kept on ice. The plasma was separated by centrifugation
for 30min, and plasma and serum samples were stored
at −80◦C until analysis. Serum syndecan-4 concentrations
were measured by sandwich enzyme-linked immunosorbent
assay (ELISA) according to the manufacturer’s protocol (IBL
Co., Ltd., Fujioka, Japan). This ELISA system recognizes
the secreted ectodomain of the syndecan-4 molecule in
blood. Plasma BNP concentration was measured with an
immunoradiometric assay (Shionoria BNP assay, Shionogi
Pharmaceutical Co., Osaka, Japan). Plasma TGF-?1 concen-
tration (R&D Systems, Minneapolis, MN, USA), serum MMP2
activity (GE Health Care Japan, Tokyo, Japan), and serum
tenascin-C concentration (IBL Co., Ltd.) were measured by
Serum syndecan-4 level in heart failure 327
Baseline characteristics of patients.
deviation or number
of patients (% of
CHF admission in previous year
ARB and/or ACEI
Plasma polypeptide hormones
Plasma BNP (pg/mL)
LV end-diastolic dimension (mm)
LV end-systolic dimension (mm)
LV end-diastolic volume (mL)
LV end-systolic volume (mL)
LV mass index (g/m2)
LA volume index (mL/m2)
ARB, angiotensin receptor blocker; ACEI, angiotensin-converting
enzyme inhibitor; BNP, B-type natriuretic peptide; CHF, chronic
heart failure; EF, ejection fraction; E/e?, early transmitral flow
velocity/early diastolic velocity of the mitral valve annulus;
NYHA, New York Heart Association; LV, left ventricle; LA, left
Two-dimensional imaging was performed according to the
recommendations of the American Society of Echocardiogra-
phy . Pulsed Doppler was used to record transmitral flow
in the apical four-chamber view . Tissue Doppler veloc-
ities were acquired at the septal and lateral annular sites
and averaged as previously described . These measure-
ments were performed using Aplio echocardiograph (Toshiba
Medical Systems Co., Ltd., Tochigi, Japan). Studies were
analyzed by an echocardiologist blinded to all clinical data.
Values are expressed as the mean±standard deviation.
Statistical analysis was performed using SPSS version 17.0
(SPSS Inc., Chicago, IL, USA). Serum syndecan-4 concentra-
tion of normal subjects and patients with heart failure was
compared using Mann—Whitney test. Multiple and simple
regression analyses were applied to determine the cor-
relation among serum syndecan-4 concentration, clinical
status, echocardiographic parameters, and other biomark-
ers associated with heart failure. Data of biomarkers were
converted by logarithmic transformation and then statisti-
cal tests were performed. The optimal serum syndecan-4
concentration was evaluated by receiver operating charac-
teristic (ROC) curve. The clinical outcomes were displayed
with Kaplan—Meier event-free curve and compared with the
use of log-rank test. A probability value <0.05 was consid-
ered statistically significant.
Clinical characteristics and serum syndecan-4
Clinical characteristics of patients with heart failure are
summarized in Table 1. Of the 45 patients with heart fail-
ure, 64% had a previous history of overt heart failure within
the past year. The highest incidence of functional status
based on the New York Heart Association (NYHA) classifi-
cation was found for class II (40%), followed by classes I
(36%), III (13%), and IV (11%). The mean left ventricular
(LV) ejection fraction (EF) (48.4±17.5%) was lower than
that of healthy subjects (72.0±5.3%, p<0.05) and the LV
mass index (142.9±40.2g/m2) of patients with heart fail-
ure was significantly higher than that of healthy subjects
Since the distribution pattern of serum biomarker con-
centration did not match with normal distribution, data
were converted by logarithmic transformation and then sta-
tration of patients with heart failure (509.7±454.3pg/mL)
was significantly higher than that of healthy subjects
(4.0±2.7pg/mL, p<0.05). Similarly, serum syndecan-4 con-
centration was significantly higher in patients with heart
failure than in healthy subjects (22.5±12.3ng/mL vs.
5.7±3.3ng/mL, p<0.01; Fig. 1). Although healthy subjects
were younger than patients, serum syndecan-4 concen-
tration was not significantly different among different
ages in healthy subjects (correlation coefficient of serum
syndecan-4 concentration and age, 0.171; ns), suggesting
that difference in serum syndecan-4 concentration between
patients and healthy subjects is not due to age difference.
Relationship between serum level of biomarkers
and echocardiographic parameters
We next determined which biomarkers represent the
echocardiographic functional and architectural parameters.
Table 2 shows the multiple correlation coefficient (R) of the
predictive equation for each echocardiographic parameter
and the partial regression coefficient (ˇ) of each biomarker
that is predictive of each echocardiographic parameter. Mul-
tiple regression analysis revealed unique correlation profiles
of echocardiographic parameters between serum syndecan-
4 and plasma BNP concentrations; only EF was correlated
328 R. Takahashi et al.
P 0 01P<0.01
Normal Heart failure
heart failure and healthy subjects. The difference in Serum
syndecan-4 concentration was compared between the two
groups by Mann—Whitney test. Statistical significance was
defined as 0.01.
Serum syndecan-4 concentration in patients with
with both of them. LV mass index, LV end-diastolic vol-
ume (LVEDV), and systolic left ventricular diameter (LVDs),
parameters of LV geometry, were correlated only with
serum syndecan-4 concentration, while early transmitral
flow velocity/early diastolic velocity of the mitral valve
annulus (E/e?), right ventricular systolic pressure (RVSP),
and left atrial volume index, parameters for blood flow and
pressure, were mainly correlated with plasma BNP concen-
Simple regression analysis also demonstrated significant
correlation of syndecan-4 with EF, LV mass index, LVEDV, and
LVDs (Figs. 2 and 3 and Table 3). These data suggest that
syndecan-4 represents a different aspect of cardiac function
from BNP, MMP2, and TGF-?1.
Relationship among biomarkers
We next examined whether syndecan-4 correlates with
other biomarkers. As shown in Table 4, serum syndecan-4
concentration did not significantly correlate with the con-
centrations of BNP, MMP2, TGF-?1, and tenascin-C.
Prognostic value of serum syndecan-4
concentration for cardiac events
During the 3-year follow-up, 10 patients were re-admitted
to the hospital due to worsening of heart failure and 5 of
them subsequently died of heart failure. The ROC curves
of serum sybdecan-4 and plasma BNP concentration for
the prediction of cardiac death or re-hospitalization due
to heart failure are shown in Fig. 4. The area under the
curve (AUC) of serum syndecan-4 concentration for the pre-
diction of cardiac death or re-hospitalization due to heart
failure was 0.706 (95% confidence interval: 0.537—0.875,
p<0.05), while that of plasma BNP concentration was 0.763
(95% confidence interval: 0.601—0.912, p<0.01). AUCs of
TGF-?, MMP2, and tenascin-C for the prediction of cardiac
death or re-hospitalization due to heart failure were 0.418,
0.639, and 0.618, respectively, and these values were not
Since the value for (1−sensitivity)2+(1−specificity)2
was minimal when the serum syndecan-4 concentration
was 18.4ng/mL, we defined this concentration as the opti-
mal cut-off point discriminating cardiac events for further
analysis. Fig. 5 shows event-free curve for high- and low-
serum syndecan-4 concentration by Kaplan—Meier analysis.
Patients with serum syndecan-4 concentration >18.4ng/mL
had a significantly lower event-free rate (p<0.01, log-rank
Biomarkers for prediction of echocardiographic parameters in multiple regression analysis.
Objective variable Multiple
Syndecan-4BNP MMP2 TGF-?1
LV mass index
LA volume index
0.004 0.316 0.029
BNP, B-type natriuretic peptide; EF, ejection fraction; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVDs, systolic
left ventricular diameter; RVSP, right ventricular systolic pressure; LA, left atrial; E/e?, early transmitral flow velocity/early diastolic
velocity of the mitral valve annulus; MMP2, matrix metalloproteinase-2; TGF-?1, transforming growth factor-beta 1. Data of biomarkers
were converted by logarithmic transformation.
Biomarkers (explanatory variables) used to predict each echocardiographic parameter (objective variables) were determined by multiple
regression analysis. Multiple correlation coefficient (R) of each predictive formula and partial regression coefficient (ˇ) of biomarkers
that are predictive of echocardiographic parameters are shown. Tenascin-C was not significantly correlated with each echocardiographic
parameter in multiple regression analysis.
Serum syndecan-4 level in heart failure329
r = -0.599
r = -0.614
P 0 001 P<0.001
1.0 2.03.0 4.0
son’s correlation coefficient of the concentration of serum syndecan-4 (A) and plasma BNP (B) with EF was calculated. Since the
distribution pattern of serum biomarker concentration did not match with normal distribution, data were converted by logarithmic
transformation and then statistical tests were performed.
Correlation of serum syndecan-4 and B-type natriuretic peptide (BNP) concentrations with ejection fraction (EF). Pear-
LV mass index
LV mass index
r = 0.315
P < 0 035
r = 0.135
0.5 1.0 2.0
P < 0.035
mass index. Pearson’s correlation coefficient of the concentration of serum syndecan-4 (A) and plasma BNP (B) with the LV mass
index was also calculated after logarithmic transformation. ns, not significant.
Correlation of serum syndecan-4 and plasma B-type natriuretic peptide (BNP) concentrations with left ventricular (LV)
Correlation between biomarkers and echocardiographic parameters in simple regression analysis.
Syndecan-4BNPMMP2 TGF-?1 Tenascin-C
LV mass index
LA volume index
BNP, B-type natriuretic peptide; EF, ejection fraction; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVDs, systolic
left ventricular diameter; RVSP, right ventricular systolic pressure; LA, left atrial; E/e?, early transmitral flow velocity/early diastolic
velocity of the mitral valve annulus; MMP2, matrix metalloproteinase-2; TGF-?1, transforming growth factor-beta 1.
330 R. Takahashi et al.
Correlation among biomarkers in simple regression analysis.
BNP, B-type natriuretic peptide; MMP2, matrix metalloproteinase-2; TGF-?1, transforming growth factor-beta 1.
0 6 0.6
0 763 0.763AUCAUC
95% CI 0.537~0.875 0.601~0.912
0 6 0.60 8 0.8
B-type natriuretic peptide (BNP) concentration for heart failure
events. The receiver operating characteristic curve was created
to predict death and re-hospitalization caused by worsening
of heart failure based on serum syndecan-4 and plasma BNP
concentration. AUC, area under the curve.
Predictive ability of serum syndecan-4 and plasma
Syndecan 4<18 4 ng/mL
S Syndecan-4>18.4 ng/mL
4 18 4
0 4 0.4
10 2030 36
syndecan-4 concentrations. Event-free rate from death and
re-hospitalization caused by worsening of heart failure was
compared between high- and low-serum syndecan-4 concen-
trations by Kaplan—Meier analysis. Cut-off level of serum
syndecan-4 concentration (18.4ng/mL) was determined by the
receiver operating curve. Statistical significance of separation
between 2 groups was achieved by log-rank test at 36 months.
Kaplan—Meierevent-freecurves for serum
This study demonstrated that serum syndecan-4 con-
centration was significantly increased in patients with
heart failure. In addition, serum syndecan-4 concentration
inversely correlated with EF and positively correlated with
geometrical parameters of LV hypertrophy and enlargement,
including LV mass index, LVEDV, and LVDs. The increase in
serum syndecan-4 concentration was a predictor of cardiac
death and re-hospitalization due to heart failure. This is
the first report to demonstrate elevated serum syndecan-4
concentration in patients with heart failure.
Heart failure results from complex architectural, cellu-
lar, and molecular changes involving necrosis, apoptosis, and
repair processes. Several humoral factors have been used
to monitor cardiac performance in the context of heart
failure. Many biomarkers are now applied to estimate the
cardiac function in the failing heart . At present, the
most representative cardiac biomarker for heart failure is
considered to be BNP, which exerts a natriuretic effect as
well as an anti-fibrotic effect . BNP is secreted mainly
from the ventricle in response to myocardial stretch, i.e.
the elevation of the LV filling pressure . BNP subse-
quently reduces hemodynamic overload in the failing heart
and inhibits fibrosis-mediated cardiac remodeling. Measur-
ing the plasma BNP level is useful to diagnose true heart
failure in patients with dyspnea during their visit to the
emergency room . It also can predict in-hospital and
postdischarge survival in heart failure patients .
Syndecan-4 has been reported to promote wound heal-
ing and angiogenesis in granulation tissue after skin injury
. In the rat experimental infarction model, mRNA lev-
els and protein amount of syndecan-4 were increased in the
noninfarcted LV tissue one week after myocardial infarction,
suggesting that syndecan-4 has the potential to promote the
hypertrophic response in the noninfarcted myocardium .
Kojima et al. reported an elevated serum syndecan-4 level
with a peak value at 2 weeks after myocardial infarction ,
which corresponds to the repair phase. They also demon-
strated abundant production of syndecan-4 protein in the
repair region, but not the undamaged or fibrous scar region
after myocardial infarction . Thus, syndecan-4 may rep-
resent an aspect of heart failure different from BNP. In fact,
our data show a significant correlation of serum syndecan-
4 concentration with LV geometrical parameters (LV mass
index, LVEDV, and LVDs), while BNP was significantly cor-
related with pressure-related parameters (E/e?, RVSP, and
LA volume, a barometer of LV filling pressure) . Since
EF is the ratio between stroke volume (a pressure-related
physiological measurement) and EDV (a geometrical mea-
Serum syndecan-4 level in heart failure331
surement), it is not surprising that both syndecan-4 and BNP
were correlated with EF. Moreover, no correlation was found
between syndecan-4 and BNP and other biomarkers, sug-
gesting that syndecan-4 is a novel independent biomarker
from BNP, MMP2, TGF-?1, and tenascin-C. Our data thus sug-
gest that serum syndecan-4 concentration may represent a
biomarker specifically for LV geometrical remodeling rather
than hemodynamic changes in the failing heart.
We next examined whether serum syndecan-4 concen-
tration has predictive power of cardiac events. During
the 3-year follow-up, 10 patients (22%) were re-admitted
to the hospital, and 5 of them (11%) died of heart fail-
ure. The AUC for the prediction of cardiac death and
re-hospitalization due to heart failure, based on serum
syndecan-4 concentration at the first hospitalization (0.706,
p<0.05), was second to that based on plasma BNP concen-
tration (0.763, p<0.01). However, since the 95% confidence
interval of serum syndecan-4 (0.537—0.875) overlapped
with that of plasma BNP (0.601—0.912), predictive power
of cardiac events of these biomarkers was not statisti-
cally different. AUCs based on concentrations of TGF-?1,
MMP2, and tenascin-C did not significantly predict death
and re-hospitalization due to heart failure. In addition,
Kaplan—Meier analysis demonstrated that patients with
serum syndecan-4 concentration >18.4ng/mL had a signifi-
cantly lower cardiac event-free rate.
Tenascin-C is a ubiquitously expressed heparan sulfate
proteoglycan that is structurally related to syndecan-4. A
recent study has reported that tenascin-C is increased in
patients with heart failure and idiopathic dilated cardiomy-
opathy . Tenascin-C and syndecan-4 are transiently
up-regulated during tissue repair and wound healing in vari-
ous tissues. Thus, this study also measured serum tenascin-C
concentration in the patient population. However, tenascin-
C concentration had a weak inverse correlation only with
EF (Table 3) and there was no significant correlation
between levels of these two proteoglycans (Table 4). Among
syndecan-4, TGF-?1, MMP2, and tenascin-C, which are
involved in ECM turnover, only syndecan-4 could predict car-
diac events, suggesting a key role of syndecan-4 in cardiac
remodeling in the context of ECM metabolism.
Approximately 50% of patients with heart failure have
preserved EF . The plasma BNP level is reportedly
higher in those patients with reduced EF than with
preserved EF . We also found significantly higher
plasma BNP concentration in patients with EF of less
than 55% (688.0±358.7pg/mL) than with EF more than
55% (164.2±147.9pg/mL, p<0.05). In contrast, serum
syndecan-4 concentration in each group was not significantly
different between patients with reduced and preserved EF
(25.9±12.8ng/mL vs. 20.7±12.9ng/mL, ns); serum con-
centrations of TGF-?1, MMP2, and tenascin-C were also not
significantly different between these two types of heart fail-
ure. These data suggest no differences in ECM metabolism
in patients with reduced or preserved EF heart failure.
Although our study indicated a significant correlation
between serum syndecan-4 concentration, other humoral
factors, and echocardiographic parameters, the relatively
small patient population limits the statistical power for
detecting the relationships between other parameters.
Thus, further investigation with a larger patient popula-
tion would be of benefit. In addition, investigation of the
source of syndecan-4 production would greatly advance our
understanding of the pathophysiology of heart failure and
Serum syndecan-4 concentration is increased in patients
with chronic heart failure, inversely correlated with EF, and
positively correlated with LV geometric parameters. Fur-
thermore, serum syndecan-4 concentration could predict
cardiac death and re-hospitalization due to heart failure.
Given that it is a co-receptor of growth factor receptors for
fibroblast growth factor-2, hepatocyte growth factor, and
platelet derived growth factor, syndecan-4 may be useful as
a biomarker for diagnosis of the LV remodeling process in
patients with heart failure.
This work was supported by Grant-in-Aid for Scientific
Research (KAKENHI B-17390224 and S-15109010) from the
Japan Society for the Promotion of Science (JSPS). RT, KN,
and AW equally contributed to this research.
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