Surgical Science, 2013, 4, 371-376 Published Online August 2013 (
Heart Valve Lesions Due to the Formation of a
Beta-Hemolytic Streptococ Role of Adhesion Molecules
Semsi Altaner1, Turhan Kurum2, Muzaffer Demir3, Burhan Turgut4, Turan Ege5, Enver Duran5
1Pathology Department, School of Medicine, Baskent University, Istanbul, Turkey
2TEM Hospital, Istanbul, Turkey
3 Hematology Department, School of Medicine, Trakya University, Edirne, Turkey
4 School of Medicine, Namik Kemal University, Tekirdag, Turkey
5School of Medicine, Trakya University, Edirne, Turkey
Received June 8, 2013; revised July 9, 2013; accepted July 18, 2013
Copyright © 2013 Semsi Altaner et al. This is an open access article distributed under the Creative Commons Attribution License,
which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Objectives: A rise in the levels of adhesion molecules such as VCAM-1, ICAM-1and E-selectin in valve disease pa-
tients has been reported lately. In our study, by detecting the presence of adhesion molecule expression in the valve en-
dothelium we will try to show the level of adhesion molecules in peripheral blood leucocytes. Materials and Methods:
Valve samples were obtained from patients having undergone aortic and mitral valve replacement due to symptomatic
aortic stenosis/aortic insufficiency and/or mitral stenosis/mitral insufficiency. The clinical preoperative diagnosis was
made using two-dimensional echocardiography and Doppler echocardiography. Rheumatic valves were in group B (n =
20). Group A (n = 8) constituted the control group. Immunohistochemical staining was performed using CD4, CD8,
CD54/ICAM-1, and CD106/VCAM-1. Flow cytometric analysis was performed. The Kolmogorov-Smirnov test and
Fisher’s exact test were used for the comparison of categorical variables. Results: Group A (non-rheumatic) patients
were found to be older than group B (rheumatic) patients (59.8 ± 11.4 years vs. 45.3 ± 11.8 years, p = 0.008). In group
B VCAM-1 level was higher than that of group A (296.6 ± 21.2 vs. 258.5 ± 42.1, p = 0.004). CD11b monocyte in group
B was higher than in group A (98.8 ± 0.5 vs. 92.9 ± 9.7, p = 0.003). CD11b granulocyte was higher in group B than in
group A (99.96 ± 0.05 vs. 93.79 ± 13.26, p = 0.33). Significant differences were not determined in the other parameters.
Conclusion: The fact that increases in serum VCAM-1 and CD-11b only occurred in patients with rheumatic valvular
disease in our study suggests that inflammation in patients with the same hemodynamic disorder is higher in rheumatic
valvular disease than in the ones with non-rheumatic valvular disease.
Keywords: Rheumatic Fever; Chronic Valve Disease; Cell Adhesion Molecules
1. Introduction
Rheumatic fever (RF) is an inflammatory disease where
the immune mechanism targets the heart following Group
A beta-hemolytic streptococcal pharyngitis [1,2]. Im-
mune response developing against streptococcal anti-
gens in the development of RF has been accepted as a
cause of initiation of the disease. Both genetic and envi-
ronmental factors are effective in the development of RF.
RF mostly reveals itself by leading to carditis. Pathologi-
cal signs of rheumatic carditis, which include Anitschkow
myocytes and Aschoff nodules, have an effect on heart
tissue [3,4]. Valve involvement is diagnosed by observ-
ing the development of verru and nodules on the mitral
valve, accompanied by edema and cellular inflamma-
The approach accepted during the past half-century
has appeared to be that Group A streptococcal antigens
may break immune tolerance in vivo as a consequence of
antigenic similarity and/or an abnormal response to this
bacterial antigen [5]. Although factors that precede the
progression of fibrosis in some patients with rheumatic
fever have not been entirely revealed, progressive fibro-
sis of valves and chronic valve disease develop in such
patients. The pathogenetic mechanisms causing RF and
non-rheumatic heart disease could still not be entirely
determined [5].
Rheumatic heart disease is the most frequent cause of
valvular diseases in developing countries [5]. Rheumatic
fever and non-rheumatic heart diseases are still an im-
portant worldwide public health problem in terms of car-
opyright © 2013 SciRes. SS
diovascular mortality and morbidity in the 21st century
[6]. Chronic rheumatic valvular disease is considered to
be a late sequela that occurs in 30% of patients with
rheumatic fever. Mitral valvulitis is the most common
lesion of acute rheumatic carditis. Valvulitis generally
occurs in the valves and chordae tendineae due to fibrous
tissue accumulation as a consequence of recovery and
disease episodes. Rheumatic fever is diagnosed in 99%
of patients who undergo mitral valve replacement due to
mitral valve stenosis [6].
There is a period of at least 2 years and generally long
intervals (10 to 20 years) between the occurrence of
rheumatic carditis attack and symptomatic valve disease
[7,8]. Primary lesions of the valve in RF patients are
translucent nodules observed along the closure lines of
the valve. The valve weakens and has a fibrotic and cal-
cified appearance due to the development of valvulitis.
Mitral valvulitis occurring due to an attack of RF causes
abnormal flow across the valve. This changing flow pat-
tern develops an increasing tension on the disordered
structure of the valve. In addition, inflammation in the
valve leads to the development of fibrin deposits on the
surface of the valve which causes an increase in the ab-
normal flow pattern across the valve. Tension and pres-
sure exerted over the course of years results in weakness
and fibrosis of the valve. Anatomical differences in pa-
tients of severe mitral stenosis (MS) or aortic stenosis
(AS) are developed by the stable and progressive trauma
caused by the turbulent flow [9]. It is still discussed
whether the development of anatomical differences in the
valve are of a progressing rheumatic origin or progress-
sive fibrosis, weakening and calcification developing in
the valve which is deformed by a turbulent flow. The
endothelial cells in the walls of large vessels, such as the
aorta, and cardiac valves are exposed to high shear stress.
Cardiac valve endothelial cells have a special morpho-
logical structure. These valves are in the form of surface
microvilli [10].
Cell adhesion molecules are special structures found
on the surface of circulating leucocytes and endothelial
cells, which regulate the migration of leucocytes to the
functionally different body tissues. These cell adhesion
molecules provide the orientation of effectors cells to the
sites of inflammation and tissue destruction, lymphocyte
circulation among lymphoid tissues and the progenitor
cell development and maturity within the hematopoietic
microenvironment [11,12]. Cell adhesion molecules in
human serum in healthy patients can be detected at very
low levels. However, there is also a group of diseases
with inflammatory or vascular etiology for which low
levels of cell adhesion molecules can be detected.
Intercellular adhesion molecule-l (ICAM-1), vascular
adhesion molecule-1 (VCAM-1) and E-selectin are
structures functioning as receptors for the inflammatory
cells which are detected circulating on the vascular en-
dothelium. ICAM is a membrane glycoprotein which
allows glycolysis at different values [13,14]. Endothelial
cells are situated on the fibroblasts, epithelial cells and
active lymphocytes. VCAM-1 are structures activated by
Interleukin-1B (IL), TNF-alpha and IL-4 situated primar-
ily on bone marrow fibroblasts, macrophages, synovial
lining cells, germinal center dendritic cells and endothe-
lial cells [15]. Selectins are structures which have a very
important role in the first contact and rolling of leuco-
cytes on the active endothelium. E-selectin is a molecule
found on endothelial cells stimulated only by cytokines
[13,14]. The increased serum levels of this molecule are
accepted as an indicator of endothelial cell activation.
Unlike other adhesion molecules which have a wider
tissue distribution, E-selectin is found only on the acti-
vated endothelium. A rise in E-selectin level will show
endothelial activation as a component of a special pa-
thology or damage. In vivo expression generally appears
along with active granulomatous inflammation and de-
layed hypersensitivity.
CD11b (Mac-1 α chain) is one of the β 2-integrins ex-
pressed on leucocytes. It mediates leukocyte adhesion
and transmigration to the endothelial cells. In addition, it
has a role in neutrophil adhesion (homotopical adhesion)
and chemotaxis.
A rise in adhesion molecule levels, such as VCAM-1,
ICAM-1and E-selectin in valve disease patients has been
reported recently [16-18]. In our study by detecting the
presence of CD11b lymphocytes in the valve tissue, ad-
hesion molecule expression in the valve endothelium and
the level of adhesion molecules in peripheral blood leu-
cocytes, we will try to show whether there is an active
inflammatory process during the chronic period of rheu-
matic fever. On the condition of the presence of the
process we will try to differentiate whether a progressive
inflammation or hemodynamic loading caused by under-
lying preload and after load increase leads to an increase
in adhesion molecules by applying the findings at tissue
2. Materials and Methods
2.1. Tissues
Valve samples were obtained from patients having un-
dergone aortic and mitral valve replacement due to sy-
mptomatic aortic stenosis/aortic insufficiency and/or mi-
tral stenosis/mitral insufficiency in Trakya University
Hospital for histopathological examination. The clinical
preoperative diagnosis was made using two-dimensional
echocardiography and Doppler echocardiography. Calci-
fied and/or fibrotic rheumatic valves were collected dur-
ing the operations. (Group B; n = 20, 11 male, 9 female).
Mitral valve tissue evaluated as ischemic during valve
Copyright © 2013 SciRes. SS
repair surgery and aortic valve tissue of non-rheumatic
etiology (Group A; n = 8, 5 male, 3 female) constituted
the control group. Patients with malignity, inflammatory
disease, renal or liver disease, diabetes mellitus, hyper-
tension, hyperlipidemia, deep venous thrombosis, pul-
monary emboli or a past history of surgery in both
groups were excluded from the study. Whether or not
calcification was present, commissural fusion and fibrous
thickening within the site of valve closures and revascu-
larization were evaluated as the macroscopic evidence of
rheumatic origin.
2.2. Immunohistochemical Study
All tissue samples were fixed with 10% neutral formalin
and embedded in paraffin. 3-µm thick sections were ob-
tained from paraffin blocks. First, the sections were de-
hydrated in series of alcohol then they were placed in a
10 mM citrate tampon and were exposed to antigen re-
trieval for 40 minutes. After heating, the sections were
left to cool at room temperature and they were washed
with tampon saline. They were treated with 3% hydrogen
peroxide in methanol for 5 minutes. Immunohistochemi-
cal marking was performed using a streptavidin-biotin
peroxidase system (DAKO LSAB kit, United Kingdom).
CD4 Ab-8 (clone 4B12, Neomarkers, United Kingdom),
CD8 Ab-7 (clone 4B11, Neomarkers, United Kingdom),
CD54/ICAM-1 Ab-4 (Clone 54CO4, Neomarkers, United
Kingdom), and CD106/VCAM-1 Ab-3 (Clone 1.4 C3,
NeoMarkers, United Kingdom) were incubated for an
hour at room temperature. Secondary antibodies were
performed for 15 minutes after rinsing with a saline
phosphate tampon. The sections were incubated with
streptavidin-biotin complex for 10 minutes and treated
for 5 minutes with a hydrogen peroxide phosphate tam-
pon. They were colored with 3.3 diaminobenzidine tet-
rahydrochloride (DAB). Mayer’s hematoxylin was per-
formed as counterstaining. Afterwards, the sections were
dehydrated with a series of ethanol performance. Cyto-
plasmatic and membranous staining was accepted as
positive for ICAM-1 and VCAM-1.
2.3. Cytokins
Blood samples were obtained in the fasting state between
9 and 10 am in the control and study groups in order to
be able to exclude the possible influence of circadian
fluctuation. Blood samples were collected in 5-ml tubes
containing 3.8% Na-citrate. Blood samples were ob-
tained under minimal tourniquet pressure from the ante-
cubital vein using a sterile 22-gauge needle syringe in a
single attempt, from the patients in the supine position
for at least 20 minutes and the samples were centrifuged
at 3000 turnover for 10 minutes at +4˚C. Plasma was
decomposed and frozen at 80˚C. Blood samples were
analyzed according to standard laboratory methods in-
cluding whole blood count, biochemical and electrolyte
measurements, and blood samples with excessive hemo-
lysis were excluded from the study. The soluble VCAM-
1 and ICAM-1 concentrations of human plasma samples
were measured by using commercially available, solid-
phase, enzyme-linked kits (Diaclone; Besancon, France).
The blood samples were processed according to the in-
structions of the manufacturer. The duration between the
collection of blood samples and antibody labeling was
standardized as an hour. Anti-VCAM-1 and anti-ICAM-1
antibodies were sequentially added after the testing sam-
ples were treated with monoclonal antibodies found in
the standard of known soluble concentrations of VCAM-
1 and ICAM-1. Unbound materials were removed and an
enzyme (streptavidin-peroxidase) was added after an
hour of incubation at room temperature. Subsequent to
incubation and washing to remove the entire unbound
enzyme, a substrate solution (chromogen [tetramethyl-
benzidine]) was added to induce a color reaction. The
color reaction was measured using a microplate reader
(Dynex Technologies; Chantilly, UK) and reading the
absorbance at 450 nm with a correction wavelength of
630 nm. A standard curve was obtained using the mean
absorbance values of VCAM-1 and ICAM-1, and the
VCAM-1 and ICAM-1 concentrations in unknown
plasma samples were calculated by linear regression. All
standards and samples were tested in duplicate. Accord-
ing to the manufacturer of the kits, the minimum quanti-
fiable doses of VCAM-1 and ICAM-1 are <0.6 ng/ml
and <0.1 ng/ml respectively.
2.4. Cell Preparation, Marking and Flow
Cytometric Analysis
Fluorescein isothiocyanate (FITC), phycoerythrin (PE)
and phycoerythrin-cyanin 5.1 (PC5) dyes with conjuge
monoclonal antibodies isotophic controls were used in
the study carried out with three colors through direct
immunofluorescence method.
Preparing the samples: The blood sample with 100 μl
EDTA was treated in a suitable way and incubated with a
monoclonal antibody cocktail at room temperature and in
darkness for 20 minutes. In addition to this, lysis of
erythrocytes and fixation of leukocytes were carried out
in a multi-Q prep workstation, Beckman Coulter, which
was an automated device for preparing samples. Analysis
was conducted using a coulter Epics XL current cytome-
try device. Expression rates of antigens on lymphocytes,
determined according to light characteristics formed on
the histogram with system II software, were measured.
2.5. Statistics
Continuous variables were described in terms of the
Copyright © 2013 SciRes. SS
mean ± SD and categorical variables were described as
percentages. The suitability of the continuous variables
with normal distribution was examined using the Kol-
mogorov-Smirnov test. In comparing variables between
the groups, a T-test was used for independent groups
with normal distribution but the Mann-Whitney U test
was used for independent groups without normal distri-
bution. Fisher’s exact test was used for the comparison of
categorical variables. P < 0.05 was considered statistic-
cally significant.
3. Results
The clinical characteristics for each patient are summa-
rized in Table 1. Group A patients were found to be
older than group B patients (59.8 ± 11.4 years vs. 45.3 ±
11.8 years, p = 0.008). In group B the ICAM-1 level was
higher than that of group A (296.6 ± 21.2 vs. 258.5 ±
42.1, p = 0.004). Group B had higher monocyte CD11b
levels in group A (98.8 ± 0.5 vs. 92.9 ± 9.7, p = 0.003).
CD11b granulocyte level was higher in group B group
than in group A (99.96 ± 0.05 vs. 93.79 ± 13.26, p =
0.33). Significant differences were not determined in
other parameters. No significant correlation between the
parameters of RVH and non-RVH could be found with
immunohistochemistry. No difference was found be-
tween gender and the diagnosis of RVH and non-RVH.
The light microscopic examination with hematoxylin
eosin revealed that the valves were observed to consist of
fibro-hyalinized tissues in wide sites. Some of the heart
valves exhibited histiocyte and lymphocyte infiltration
and in some of them young connective tissue prolifera-
tion existed. In all heart valves there were small-sized
vascular structures which were not so intense. There
were no differences in both groups at the light micro-
scopic level.
In immunohistochemical studies, CD4 or CD8 cyto-
plasmic positivity was detected in some of the lympho-
cytes, making clusters in patches located in valvular
stroma. In some lymphocytes, fibroblasts and endothelial
cells, rare CD54 (ICAM-1) cytoplasmic positivity was
detected. CD106 (VCAM-1) positivity was observed in
vascular endothelial cells and some fibroblasts.
4. Discussion
Rheumatic fever is a multi-systemic inflammatory dis-
ease occurring following group A beta-hemolytic strep
Table 1. CD4, CD8, ICAM-1 and VCAM-1 distribution of
non-rhe umatic and rh e umatic groups.
(Group A (non-rheumatic) (n = 8) 1 1 1 2
Group B (rheumatic) (n = 20) 7 5 5 10
toccal pharangitis and it commonly affects the heart. It is
also triggered by immunological mechanisms. Recurrent
streptococcal pharyngeal infections after a previous at-
tack increases the reactivation risk of the disease. The
number of lymphocytes causes an increase both in car-
diac valves and in peripheral blood and also the cytokine
levels in blood increase during acute rheumatic carditis.
In this course, adhesion molecules play a considerable
role. Intracellular adhesion molecules (ICAM-1), vascu-
lar cell adhesion molecules (VCAM-1) and E-selectin
exist in the vascular endothelium and act as ligands for
surface receptors of circulating inflammatory cells [11,
It is known that adhesion molecules differentiate their
antigenic expression according to their activation status
and location [19,20]. Detailed pathological investigations
researching the circulating forms of VCAM-1, ICAM-1
and E-selectin in the plasma have revealed the increased
expression of cellular adhesion molecules in endothelial
cells and other tissue types [21-23].
Yetkin et al. compared 34 patients who underwent
balloon mitral valvuloplasty with 34 healthy people par-
ticipating as the control group [18]. In their study the
serum levels of E-selectin, ICAM-1 and VCAM-1 were
found to be elevated in patients with mitral stenosis
compared with the control group. According to this result,
they proposed that E-selectin, ICAM-1 and VCAM-1,
which were the elevated serum adhesion molecules, are
indicators of ongoing chronic inflammation in patients
with significant rheumatic mitral stenosis. The research-
ers subsequently examined the values in the patient
group before and after the procedure and found that after
PMBV procedure, VCAM values were elevated, E-se-
lectin values had decreased and ICAM remained un-
changed. They proposed with respect to this result that
ICAM-1, VCAM-1 and E-selectin exhibit discrete
changes as a response after percutaneous mitral balloon
valvuloplasty [24]. They indicated that further investiga-
tions should be required to clarify the mechanism of the
relationship between adhesion molecules and PMBV in
addition to rheumatic mitral stenosis. Chen et al. pro-
posed that serum VCAM-1 level decreased significantly
after PMBV and elevated plasma VCAM-1 level was
related to hemodynamic abnormality, not rheumatic ac-
tivity [25].
Shahi et al. determined that soluble adhesion mole-
cules such as ICAM-1, VCAM-1 and E-selectin are ele-
vated in non-rheumatic aortic valvular stenoses. The au-
thors proposed that the pathogenesis of non-rheumatic
aortic stenosis which had been believed to be degenera-
tive actually had an inflammatory and immunologic eti-
ology. No study investigating the tissue and serum levels
of cell adhesion molecules of patients with rheumatic
aortic valvular disease was detected in literature.
Copyright © 2013 SciRes. SS
In the above mentioned studies because no immuno-
chemical studies were performed on the valvular tissues
of patients with mitral or aortic valvular diseases, and
because the relationship between serum levels was not
investigated, it could not established whether these find-
ings resulted from hemodynamic disorders or from de-
genaration. We determined that VCAM-1 in serum levels
increased in patients with rheumatic valvular disease
compared to the ones with non-rheumatic valvular dis-
ease. No significant difference was found in other adhe-
sion molecules from the serum examination. Hence, we
assume that hemodynamic disorders may have an in-
creasing effect on cell adhesion molecules in addition to
Roberts et al. tried to clarify the immunity-mediated
mechanism in rheumatic heart disease caused by group A
streptococcal infection by analyzing anti-CD4, anti-CD8
and VCAM-1 in valvular tissues acquired from 6 patients
with rheumatic valvular disease requiring valvular re-
placement (2). Out of the 6 patients, only 2 had an endo-
thelium suitable for examination. They detected that CD4
and CD8 lymphocytes penetrated through the subendo-
thelial layer on the valve surface and attached to the
valve endothelium. They proposed that T cell extravasa-
tion through the surface endothelium into the valve
seemed to be an important process in rheumatic heart
disease development. The researchers anticipate that
lymphocytic infiltration through valve surface endothe-
lium is a potential triggering step in disease pathogenesis.
However, there was no information about the serum val-
ues of the patients in this study. Mitral valves taken from
3 in order to control autopsy subjects were studied. As
for our study in the same patient group with mitral steno-
sis and/or mitral failure and/or aort stenosis and/or aort
failure, examination was performed for adhesion mole-
cules both in valvular tissue and soluble adhesion mole-
cules in blood. However, in our study, ICAM-1, VCAM-
1 and E-selectin were analyzed using IHK method both
in patients with ischemic and degenerative valvular dis-
ease and in the ones with rheumatic valvular disease, and
no significant difference was found.
Ghaisas et al. studied ICAM-1, VCAM-1 and E-se-
lectin expression via immunohistochemical method in
patients with non-rheumatic aortic disease requiring aor-
tic valvular replacement. They also analyzed the serum
values before and after surgery. They reported that adhe-
sion molecules located in the tissues increased. E-se-
lectin increased both in serum and tissue. As a cones-
quence, they proposed that the expression of adhesion
molecules in the involved valves supported the inflame-
matory component theory in degenerative aortic valvular
disease and this was the main source for E-selectin lo-
cated in the serum [17].
Muller et al. investigated the expression of cell adhe-
sion molecules using immunohistochemical method in
degenerative cardiac valves and the endothelial cells of
heart valves with endocarditis [26]. As expected, ICAM-
1, CD34 and CD31 were found both in degenerated and
inflamed valves. Muller et al. detected that significant
expressions of E-selectin and VCAM-1 were not only in
inflamed cardiac valves but also in the majority of de-
generated valves not exhibiting the morphological signs
of inflammation. They thought that they could present
this as an attractive finding to explain why fibrotic car-
diac valves were prone to recurrent endocarditis. Also,
they proposed that further investigation was required to
discover why E-selectin and VCAM-1 which are endo-
thelial activation markers were also expressed in degen-
erated cardiac valves [26].
Wallby et al. investigated T lymphocyte infiltration by
comparing the patients with degenerative calcification of
tricuspid aortic valves to patients with congenital bicus-
pid aortic valve secondary calcification [27]. Conse-
quently without considering valvular anomaly, by deter-
mining T lymphocyte infiltration in acquired aortic
stenosis equally, they proposed that T lymphocyte infil-
tration should be regarded in inflammation pathogenesis.
Finally, none of these studies examined or compared
rheumatic and non-rheumatic valvular disease in terms of
serum and tissue values. That only serum VCAM-1 and
tissue CD11b increases occurred in our study in patients
with rheumatic valvular disease suggests that inflamma-
tion in patients with the same hemodynamic disorder is
higher in rheumatic valvular disease than in the ones with
non-rheumatic valvular disease.
Restrictions: The values for rheumatic and ischemic
valvular diseases were not compared with the normal
control group. Average values were above the cut-off
level. In addition, control values were not examined after
valvular changes. For this reason, whether hemodynamic
improvement occurred or not cannot be shown with the
serum values.
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