ORIGINAL ARTICLE

Evaluation of serum anti-cardiolipin antibodies after non-surgicalperiodontal treatment in chronic periodontitis patients

Farin Kiany • Azita Hedayati

Received: 8 March 2013 / Accepted: 9 January 2014

� The Society of The Nippon Dental University 2014

Abstract The present study investigated the effect of

non-surgical periodontal therapy on serum level of anti-

cardiolipin antibodies (aCLA), which are potentially

involved in the pathogenesis of cardiovascular diseases in

periodontal patients. Twenty volunteers (11 females and 9

males) with the mean age of 40.55 years participated in

this study. Generalized chronic periodontitis was diagnosed

through clinical periodontal examination at baseline visit.

This examination included measuring the probing pocket

depth and clinical attachment loss. Plaque index and gin-

gival index were also recorded. After baseline examination,

all the subjects received full-mouth non-surgical peri-

odontal treatment. Subjects returned for a final visit

6 weeks after the last session of scaling for reevaluation of

the periodontal parameters. At baseline and final visits 2 ml

of venous blood was collected from each patient and an

available commercially enzyme-linked immunosorbent

assay was used for analyzing aCLA (IgM and IgG). The

collected data were analyzed using the paired sample t test.

Mean levels of both forms of aCLA, before and after

treatment, showed statistically significant difference

(P = 0.003 for IgM and P = 0.001 for IgG). In addition,

study results showed significant reductions in periodontal

parameters after non-surgical periodontal therapy

(P \ 0.001). The results of this study suggested that suc-

cessful periodontal therapy can improve the serum level of

one of the inflammatory biomarkers involved in the car-

diovascular problems.

Keywords Anti-cardiolipin antibodies � Chronic

periodontitis � Cardiovascular diseases � Antiphospholipid

syndrome � Periodontal treatment

Introduction

Recently, the relationship between oral and systemic dis-

eases has become a major concern, specifically the asso-

ciation between periodontitis and cardiovascular diseases

[1]. Several pathophysiologic mechanisms are reported to

be associated with periodontal diseases and atheromatous

lesions [2]. Among these pathological pathways, inflam-

matory and hemostatic processes are the most interesting

[3]. Periodontal disease is a chronic inflammatory disease

that affects the gingival tissues and supporting bone around

the teeth. Periodontitis is a more severe form of periodontal

disease and a recent report in the United States estimates

that 64.7 million of American adults suffer from peri-

odontitis [4]. It has also been suggested that severe gen-

eralized periodontitis can be found in 8–13 % of the

world’s adult population [5]. Periodontitis is initiated by

the colonization of bacterial plaque around the cervical

tooth surfaces and the gingival tissues, thus triggering an

inflammatory response that affects the supporting peri-

odontal tissues resulting in loss of supporting bone and

finally leading to tooth loss [6].

Based on recent reports, the incidence of some systemic

disorders like cardiovascular, cerebrovascular and pul-

monary diseases, diabetes, and the chance of bearing pre-

term low-birth weight babies and fetal loss may increase in

patients with periodontitis [6, 7]. A fourfold increase in the

F. Kiany

Oral and Dental Health Care Research Center,

Shiraz University of Medical Sciences, Shiraz, Fars, Iran

F. Kiany � A. Hedayati (&)

Department of Periodontics, School of Dentistry, Shiraz

University of Medical Sciences, Shiraz, Fars, Iran

e-mail: azth_62@yahoo.com

123

Odontology

DOI 10.1007/s10266-014-0149-2

incidence of myocardial infarction among persons affected

by periodontal diseases has been reported [8]. Thus, the

association between periodontal diseases and cardiovas-

cular diseases becomes particularly a major concern in

developing countries, where a high prevalence of peri-

odontal diseases is seen [9].

Antiphospholipid antibodies (APA) comprise a class of

autoantibodies found in 1–5 % of the systemically healthy

population [10]. In several conditions, especially infectious

diseases, elevated levels of these antibodies are noticed.

APAs are the major components of antiphospholipid syn-

drome (APS) and the prothrombotic activity of some of

these antibodies comprises the hallmark of the pathogen-

esis of APS [11].

Based on this pathogenesis, the most significant clinical

symptoms of APS include recurrent venous or arterial

thrombosis, premature atherosclerosis and fetal abortion

[9]. In fact, APS is considered as a major contributor to

acquired hypercoagulable state [12, 13].

One of the major antibodies present in the APS patients

is anti-cardiolipin antibody (aCLA) [14]. This antibody is

directed at a natural anticoagulant that comprises b2-gly-

coprotein-I-dependent phospholipid (b2GPI). This

phospholipid plays a significant role in the regulation of

platelet function and destruction, although its exact func-

tion is still not clearly defined [15]. It is thought that a

physiologic function of b2GPI may be to protect damaged

endothelial cell surfaces from promoting improper coagu-

lation. On the other hand, b2GPI binds to anionic lipids

such as cardiolipin to form a complex which can be rec-

ognized by aCLA [16]. Cardiolipin is a very minor part of

most mammalian membranes, but a major compartment of

the inner mitochondrial membranes. It is also present in

eukaryotic organisms and some prokaryotic bacteria [17].

Clinical tests for APS usually include multiple assays for

the detection of aCLA. It is well known that aCLA is

produced in high levels in patients with autoimmune and

thromboembolic diseases. Also, patients with some viral

infections or those taking certain drugs have elevated levels

of aCLA in the absence of systemic diseases [18].

Some bacterial and viral infections are involved in the

etiology of APS. These infections act through the induction

of cross-reactive aCLA [19].

Negatively charged cardiolipins are also the targets of

immune responses, provoked by periodontal pathogens. In the

pathogenic pathway of periodontitis, the interaction of

inflammatory mediators and cardiolipin phospholipids takes

place and complement and coagulation systems are activated,

increasing the risk of thromboembolic events [15, 20].

Different studies reported that aCLA were involved in

the etiology of several systemic disorders such as throm-

bosis, stroke, myocardial infarction, atherosclerosis, mul-

tiple abortions and thrombocytopenia [21, 22].

Other recent studies assessed the level of aCLA together

with the periodontal parameters in the cardiovascular

patients. These studies revealed that elevated concentra-

tions of aCLA, increased pocket depth and clinical

attachment loss are major risk factors for stroke [15, 23]. In

addition, some related studies have evaluated the level of

aCLA with the presence and severity of periodontal dis-

eases in patients with acute myocardial infarction [24],

hypertension [22] as well as in patients with chronic [19]

and aggressive periodontitis [25].

There are significant similarities between the major

symptoms of APS and systemic consequences of peri-

odontal infections. Because of the infectious origin of the

aCLA, it has been suggested that elevated levels of these

antibodies in periodontal patients may partly explain the

pathogenesis of systemic sequelae of periodontitis in these

patients [19].

This study was planned based on the hypothesis that

systemic inflammation caused by chronic periodontitis

affects the concentration of serum aCLA. The aim of the

study was to assess the possibility that periodontal treat-

ment could reduce the serum level of aCLA which could

potentially be involved in the pathogenesis of cardiovas-

cular diseases in periodontal patients. It is speculated that if

periodontal pathogens in bacterial plaque are responsible

for these systemic responses, then serum levels of these

antibodies should decline following periodontal treatment.

Materials and methods

Study design and patient selection

The study was an interventional uncontrolled clinical trial

and was approved by the Ethics Committee of Shiraz

University of Medical Sciences. The study group consisted

of 20 patients with generalized chronic periodontitis. They

were selected among the patients referred to the Periodon-

tics Department of the Dental School of Shiraz University

of Medical Sciences. All participants had a minimum of 5

teeth per quadrant and signed informed consent acknowl-

edging their willingness to participate in the study. Patients

who were pregnant or breast feeding, presented with dis-

eases of the immune system, bleeding disorders, systemic

diseases such as cardiovascular disease, diabetes, respira-

tory infections, rheumatoid arthritis, or SLE; took medica-

tions that might affect their periodontal status or received

periodontal treatment in the preceding 6 months were

excluded from the study. All the volunteers received a full-

mouth periodontal examination, except for the third molars,

to measure the probing pocket depth (PD) and clinical

attachment loss (AL). One trained examiner performed

these measurements at six sites per teeth (mesiobuccal,

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123

buccal, distobuccal, mesiolingual, lingual and distolingual).

The periodontal examination was conducted using a Wil-

liams probe and the measurements were approximated to

the nearest millimeter. Also plaque index of Silness and Loe

(PI) [26] for assessing supra-gingival plaque and gingival

index of Loe and Silness (GI) [27] for detecting the gingival

inflammation were performed for all teeth.

Generalized chronic periodontitis was diagnosed upon

complete periodontal examination and according to the

American Academy of Periodontology Classification [28].

After baseline examination, all the participants received

full mouth non-surgical periodontal treatment, including

oral hygiene instructions, scaling and root planning and

gingival curettage, if needed. Periodontal treatment was

completed in 1–3 visits based on each patient’s requisites.

During the follow-up periods, patients were asked to report

any oral or systemic complications. Subjects returned for a

final visit and clinical periodontal parameters measure-

ments 6 weeks after the last session of scaling. CAL was

not measured at the final visit, because it is not usually

expected to record the gain of attachment in such short

period of follow-up and subsequent to initial non-surgical

periodontal treatment. At baseline examination and at final

visit, 2 ml of venous blood was collected from each

patient. Using a 20-gauge needle with a 2-ml syringe,

blood was obtained from the antecubital fossa by veni-

puncture method and transferred to the evacuated tube

containing anti clot-activating factors. The tubes were

immediately transferred to a laboratory.

aCLA (IgM and IgG) analysis

In the laboratory the blood samples were centrifuged to

separate the sera. After separation, the serum samples were

used immediately or stored tightly closed at 2–8 �C up to

3 days, or frozen at -20 �C for longer periods. The AE-

SKULISA Cardiolipin-Check solid phase enzyme immu-

noassay employing highly purified cardiolipin plus human

b2-glycoprotein I was used for the combined quantitative

and qualitative detection of IgG and IgM antibodies against

cardiolipin in human serum. aCLA mainly recognize spe-

cific epitopes on a complex composed of cardiolipin and

b2-glycoprotein I, which are expressed only when b2-

glycoprotein I interacts with cardiolipin. In the first step of

the laboratory procedure, separated serum samples diluted

1:10 were incubated in the microplates and coated with the

specific antigen. If antibodies were present in the patient

specimens they bound to the antigen on the microplate and

the unbound fraction was washed off. Afterwards anti-

human immunoglobulins conjugated to horseradish per-

oxidase (conjugate) were incubated and allowed to react

with the antigen–antibody complex in the microplates.

Unbound conjugate was washed off. The enzymatic

colorimetric (blue) reaction generated by the addition of

TMB-substrate was stopped by diluted acid (color changes

in yellow). The rate of color formation from the chromogen

was a function of the amount of conjugate bound to the

antigen–antibody complex and that was proportional to the

initial concentration of the respective antibodies in the

patient sample.

Statistical analysis

The concentrations of IgM and IgG aCLA before and after

periodontal treatment were analyzed using the paired

sample t test. The relation between clinical parameters

before and after treatment was also estimated through

paired sample t test. All data analysis was performed using

a statistical package (SPSS, version 14.0, Chicago, IL,

USA). P B 0.05 was considered statistically significant.

Results

Twenty volunteers participated in this study. Of these, 11

were females and 9 were males. The age range of the

participants was from 30 to 56 years with a mean range of

40.55 (SD = 7.93). The mean serum levels of IgM and IgG

aCLA, shown in Table 1, were 3.64 ± 1.56 and

6.36 ± 2.10 for IgM and IgG before treatment. The levels

after treatment were 2.96 ± 1.22 and 5.54 ± 1.65 for IgM

and IgG, respectively. Mean levels of both forms of aCLA

before and after treatment showed statistically significant

reduction (P = 0.003 for IgM and P = 0.001 for IgG). A

Table 1 Serum IgM and IgG aCLA Levels (mean ± SD) before and

after treatment

aCLA levels Before treatment After treatment P

IgM aCLA (IU/ml) 3.64 ± 1.56 2.96 ± 1.22* 0.003

IgG aCLA (IU/ml) 6.36 ± 2.10 5.54 ± 1.65* 0.001

aCLA anti-cardiolipin antibody

* Significant difference between before and after treatment levels by

the paired sample t test (P \ 0.05)

Table 2 Clinical periodontal parameters (mean ± SD) before and

after treatment

Clinical parameters Before treatment After treatment P

PD (mm) 6.73 ± 0.85 4.29 ± 1.04* \0.001

PI 2.48 ± 0.39 1.61 ± 0.43* \0.001

GI 2.42 ± 0.25 1.47 ± 0.42* \0.001

PD pocket depth, PI plaque index, GI gingival index

* Significant difference between before and after treatment clinical

parameters by the paired sample t test (P \ 0.05)

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significant difference (P \ 0.001) was also observed in PD,

plaque and gingival indices after non-surgical periodontal

therapy as shown in Table 2.

Discussion

Based on the observational studies, there is strong evidence

about the association between periodontitis and increased risk

of cardiovascular and cerebrovascular diseases, including

myocardial infarction and stroke, although a causal link has

not yet been fully proved [29]. There are several reports about

the increased incidence of periodontal diseases regardless of

being characterized as probing depth, attachment loss,

bleeding on probing, the number of remaining teeth or any

combinations of above in subjects with coronary heart dis-

eases [30–33]. It is noteworthy that in most studies, the

association between periodontitis and coronary heart diseases

were independent of established common risk factors such as

diabetes and smoking or other suggested coronary heart dis-

eases risk factors, such as body mass index, serum lipid

chemistry, hypertension, age and gender [31–33]. Based on

the results of these studies, investigators have claimed that

known major risk factors of atherosclerotic diseases did not

always define the pathogenesis of every atherosclerotic event,

so other novel risk factors such as inflammatory markers have

been proposed. It is now well known that inflammation takes

part in all phases of atherosclerosis [34].

Based on the critical role of inflammation, inflammatory

diseases such as periodontitis have attracted more attention.

Chronic exposure to periodontal pathogens, particularly

Gram-negative bacteria, enhances systemic production of

inflammatory mediators [19]. There is either direct

involvement of bacterial lipopolysaccharides and inflam-

matory cytokines in the pathogenic process of atheroscle-

rosis or indirect effect of antibacterial immune response

[35]. Also atheroma formation is directly and indirectly

influenced by periodontal pathogens [19].

More definitely, the low-grade bacteremia and endo-

toxemias which happen in periodontitis patients have sys-

temic effects on vascular physiology [23]. Periodontal

pathogens or their products may have a direct effect on

endothelial cells via transient bacteriemia or there maybe

indirect action of inflammatory products on endothelial

cells [36]. In other words, the burden of antigens, endo-

toxins and inflammatory cytokines are produced by the

periodontal pathogens contributing to the process of ath-

erogenesis and thromboembolic events [37]. In cardiovas-

cular patients with periodontal diseases, the atherosclerotic

plaque was reported to be associated with viable microor-

ganisms. These pathogens can enter the circulation and

induce thromboembolic events like ulceration, thrombosis,

and apoptosis of vascular cells [15].

A significant proportion of these thrombotic events can

be attributed to the presence of aCLA [38]. b2GPI as a

natural anticoagulant binds to negatively charged phos-

pholipids in the vessel wall endothelium under normal

conditions. This combination provides a protective

homeostatic mechanism and prevents thrombus formation.

When aCLA is directed against b2GPI, there is an

increased risk of venous/arteriole thrombosis formation

through disruption of coagulation homeostasis [29]. By this

interaction of aCLA with b2GPI, a thrombotic predispo-

sition may occur [39, 40].

It has been hypothesized that some aCLA found in

patients without autoimmune diseases may result from

molecular mimicry of microbial origin [2]. Some bacteria

and viruses have phospholipid-binding proteins that func-

tion like b2GPI in inducing the production of APA and

particularly anti-b2GPI antibodies. This is because of

molecular similarity between these proteins [41].

For example, some specific periodontal pathogens like

Aggregatibacter actinomycetemcomitans (formerly Acti-

nobacillus actinomycetemcomitans) and Porphyromonas

gingivalis have a peptide sequence similar to that of b2GPI

molecule [15]. These periodontal infections can provoke

antibody production that is cross-reactive with b2GPI.

Furthermore, there is evidence that b2GPI is immunogenic

and probably complicating the immune responses [42].

Petri [10] stated that aCLA is present in 1–5 % of healthy

adult population and its clinical adverse effects are not

always manifested. There are several studies that report

elevated levels of aCLA in patients with chronic peri-

odontitis and generalized aggressive periodontitis in com-

parison with healthy controls and those with localized

aggressive periodontitis [19, 43]. Schenkein et al. [19]

correlated this elevated level of aCLA with the amount of

periodontal destruction. In their study, elevated levels of

aCLA were associated with greater mean level of attach-

ment loss and increased pocket depth. In another study

systemic markers of vascular inflammation in patients with

aggressive periodontitis were associated with elevate levels

of aCLA [25].

The suggestion that periodontitis is a potential risk

factor for thrombotic events, raises a basic question whe-

ther periodontal treatment will reduce the risk of cardio-

vascular and cerebrovascular diseases.

There is limited evidence to show the beneficial effects

of periodontal therapy on cardiovascular disease outcomes

[23]. There have been some efforts to assess the effect of

periodontal treatment on the improvement of endothelial

dysfunction, the reduction of inflammatory biomarkers

related to cardiovascular diseases (including C-reactive

protein, interleukin-6), and carotid intima–media thickness.

These studies showed positive results. Most of these

interventional studies concluded that the body’s

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inflammatory burden can be reduced by periodontal treat-

ment [15–23, 44–50].

Gunupati et al. [24] investigated the effect of peri-

odontal therapy in patients with acute myocardial infarc-

tion and chronic periodontitis and showed significant

alterations in the serum levels of IgG and IgM aCLA.

We are not aware of the studies that have measured

changes of serum levels of IgM and IgG aCLA after

scaling and root planning in chronic periodontitis patients.

This study showed a statistically significant decrease in

the serum levels of IgM and IgG aCLA after non-surgical

periodontal treatment.

Turkoglu et al. [22] considered elevated concentrations

of serum IgM aCLA [15 MPL units and IgG aCLA [10 GPL units as risk factor for cardiovascular diseases.

Also according to Amoroso et al. [51] IgG aCLA\20 U/ml

is considered low and antibody titers C20 U/ml is known

as medium to high. Although, in the present study, the

serum levels of these two antibodies were lower than the

aforementioned values, periodontal treatment was effective

in lowering the concentration of the antibodies.

In the current study non-surgical periodontal treatment,

without any systemic or local adjunctive antimicrobial

therapy, resulted in a statistically significant improvement

in the clinical periodontal parameters including the mean

of PD, GI and PI. These results were in accordance with

those found by Bokhari et al. [52] and Gunupathi et al.

[24] who reported that the control of local inflammation

would lead to a reduction in the systemic acute-phase

response. Achieving these meaningful periodontal treat-

ment results, reflects the important beneficial aspect of

periodontal treatment on systemic conditions in this

clinical trial study. Improvement in periodontal parame-

ters such as PD and GI reveals the clinical reduction of

local inflammation in periodontal tissues. So it can be

postulated that the changes in gingival inflammation and

plaque accumulation are partly attributed to the alterations

in aCLA levels before and after treatment. This means

that continuous exposure to Gram-negative bacteria and

lipopolysaccharide can cause the release of cytokines such

as TNF-a, IL-1b and PGE-2. These cytokines in turn

contributed to an increase in the net rate of aCLA

expression by the activation of endothelial cells. Upon

cross-reactivity, the release of cytokines might cause

interference in the natural anticoagulant function of

b2GPI from the gingival tissues. This could be one of the

sources of circulating aCLA in periodontitis patients [15].

Also the production of aCLA could be a component of

the host defense mechanism. As a part of the immune

response, body counteracts the periodontal inflammation

by elevating the level of aCLA [19, 22]. It should be

emphasized that initial periodontal treatment did not

result in either complete pocket elimination or total arrest

of inflammation in the periodontium. Then it can be

speculated that residual inflammation did not allow a

more striking reduction of aCLA levels. Hence estab-

lishing a well-defined clinical end-point for periodontal

treatment, with minimal inflammation should be the

hallmark of periodontal therapies.

Because of the relatively small number of subjects in the

current study, there was no attempt to categorize the

patients on the basis of the severity of periodontitis. During

patient selection, only the presence of chronic periodontitis

was considered, so there were different levels of attachment

loss ranging from 2 to more than 5 mm. A larger number of

participants with greater periodontitis severity might be

associated with higher levels of antibodies at baseline and a

more significant reduction after effective treatment. Also it

should be mentioned that other systemic conditions sus-

pected to lead to the production of aCLA were excluded

from the study to reduce confounding factors. Exclusion of

these conditions may be the reason for relatively low levels

of antibodies expressed by the patients.

The present study does not address the pathogenicity or

function of the aCLA found in periodontitis patients, but it

shows that the treatment which results in the decrease of

the periodontal infection and inflammation can reduce

serum inflammatory biomarkers associated with cardio-

vascular diseases.

However, it should be emphasized that moderate or

abnormal levels of such antibodies could be pathogenic and

involved in the induction of adverse systemic outcomes of

periodontitis. Also, it can be postulated that in more severe

forms of periodontitis with greater extent of inflammation

and bone loss, the production of aCLA would increase.

Our findings suggest severity of periodontitis should be

considered when assessing the risk factors of coronary

heart diseases, stoke and adverse pregnancy outcomes.

Furthermore, recognition and treatment of periodontal

diseases should become a part of routine therapy of those

patients with the stated diseases.

Conclusions

While the impact of periodontal treatment on cardiovas-

cular events remains to be determined, the results of this

study suggest that periodontal therapy can reduce the

serum level of one of the inflammatory biomarkers

involved in cardiovascular problems. A decrease in serum

values of aCLA following periodontal treatment suggests

that the presence of pathogens contribute to elevated aCLA

in the body. Hence, the prevention and treatment of peri-

odontitis may reduce cardiovascular diseases. The results

of the present study suggest that periodontal disease is a

risk indicator for coronary heart disease.

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123

This investigation does not provide the clinical evidence

that the reduction of antiphospholipid antibodies is related

to the reduction of their adverse systemic outcomes, but it

signifies that clinicians and patients should be aware of this

association and the potential beneficial outcomes of peri-

odontal intervention.

Acknowledgments The authors thank the Vice-Chancellery of

Shiraz University of Medical Sciences for supporting this research

(Grant #3826). This manuscript is based on the thesis of Dr. Azita

Hedayati. The authors would like to thank Dr. Shahram Hamedani

(DDS, MSc) from the Dental Research Development Center and Dr.

Ehya Amal saleh for editorial suggestions and English writing

assistance and Dr. Mehrdad Vossoughi for the statistical analysis.

Conflict of interest The authors declare they have no conflict of

interest. No other funding, except that of the institution of the authors,

was provided.

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