Serum Antibody Levels to Actinobacillus

actinomycetemcomitans Predict the Risk for

Coronary Heart Disease
Pirkko J. Pussinen, Kristiina Nyyssonen, Georg Alfthan, Riitta Salonen,
Jari A. Laukkanen, Jukka T. Salonen
ObjectiveThe association between serum antibody levels to major periodontal pathogens and coronary heart disease
(CHD) was analyzed in a prospective population-based study.
Methods and ResultsThe population comprised 1023 men (aged 46 to 64 years) in the Kuopio Ischemic Heart Disease
Study. The subjects with CHD at baseline (n113) were more often seropositive for Porphyromonas gingivalis IgA
(38.9% versus 28.5%, P0.021) and IgG (60.2% versus 46.7%, P0.007) than those without CHD. During the 10-year
follow-up, 109 men free from CHD at baseline experienced an acute myocardial infarction or CHD death. The men with
an end point were more often seropositive for Actinobacillus actinomycetemcomitans IgA (15.5% versus 10.2%,
P0.019) than those who remained healthy. In the highest tertile of A. actinomycetemcomitans IgA-antibodies
compared with the lowest one, the relative risk (RR) for an end point adjusted for CHD risk factors was 2.0 (95%
confidence interval [CI], 1.2 to 3.3). In the Porphyromonas gingivalis IgA-antibody tertiles, the highest RR of 2.1 (1.3
to 3.4) was observed in the second tertile. All antibody levels correlated positively with the carotid artery intima-media
thickness.
ConclusionsHigh-serum antibody levels to major periodontal pathogens are associated with subclinical, prevalent, and
future incidence of CHD. Periodontal pathogens or host response against them may contribute to the pathogenesis of
CHD. (Arterioscler Thromb Vasc Biol. 2005;25:833-838.)
Key Words: atherosclerosis cardiovascular diseases infection inflammation periodontitis

eriodontitis is a common bacterial infection of the toothsupporting tissues. The prevalence of severe periodontitis
is 10% to 15% in most populations and it increases with age.1
The host response to the persistent bacterial insult in periodontitis leads to chronic inflammation, which causes the
symptoms of the disease: gingival bleeding, formation of
deepened periodontal pockets, destruction of tooth attachment, and eventually loss of tooth. Bacteria, their components, and local inflammation may act as triggers leading to
systemic inflammation. This can be observed as elevated
concentrations of acute-phase reactants and inflammatory
mediators, especially C-reactive protein, which has been
shown to be directly associated with atherosclerosis.2
A selection of epidemiological studies from the past
decade suggests that periodontitis is an important risk factor
for coronary heart disease (CHD).3 Most of the literature is
based on clinical periodontal examinations or self-reported
periodontitis. Therefore, interpretation of the results may
experience the absence of standard measures for periodontal

disease. However, data on the role of periodontal pathogens

in atherogenesis is limited, although some bacterial species
have been identified as etiologic agents in periodontitis.4 In 3
recent serological studies, however, high antibody levels to a
periodontal pathogen, Porphyromonas gingivalis, have been
found to associate with prevalent CHD,5 high degree of
stenosis in plaque segments,6 and incidence of acute myocardial infarction (AMI) in a small study population.7
The aim of the study was to analyze if antibody levels to
the major periodontal pathogens, Actinobacillus actinomycetemcomitans and P. gingivalis, are associated with the risk of
CHD and carotid intima-media thickness (IMT) in a prospective population-based study.

Subjects and Methods

A total of 2682 men were enrolled in the Kuopio Ischemic Heart
Disease Risk Factor (KIHD) study conducted in Finland between
1984 and 1989.8 Data on socioeconomic status were collected during
this examination. The Research Ethics Committee of the University
of Kuopio approved the study, and all study subjects gave their
written informed consent.

Original received November 5, 2004; final version accepted January 11, 2005.
From the Institute of Dentistry (P.J.P.), University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki University Central
Hospital, Helsinki; the Research Institute of Public Health (K.N., R.S., J.A.L., J.T.S.), University of Kuopio; the Department of Health and Functional
Ability (G.A.), National Public Health Institute, Helsinki; Savonlinna Central Hospital (J.A.L.), Savonlinna; and Oy Jurilab Ltd (J.T.S.), Kuopio, Finland.
Correspondence to Pirkko Pussinen, Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial Diseases, Helsinki
University Central Hospital, P.O. Box 63, FI-00014 Helsinki, Finland. E-mail pirkko.pussinen@helsinki.fi
2005 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org

DOI: 10.1161/01.ATV.0000157982.69663.59

833
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April 2005

Study Design, Population, and Outcome

The present study population comprises 1023 men aged 46 to 64
years, who were enrolled in 1987 to 1989 and re-examined after 4
years in 1991 to 1993 (baseline).9
The subjects visited the study site of re-examination (1991 to
1993) twice with a 7-day interval. Blood pressure and body mass
index were measured at the first visit. The IMT of the common
carotid artery was scanned ultrasonographically and blood samples
were drawn at the second visit.9 A self-administered questionnaire
provided information on sociodemographic background, diseases,
medication, and smoking habits.
Data on deaths were obtained from the National Death Certificate
Register, and underlying cause of death was taken as that assigned at
the Central Statistical Office of Finland. Data on nonfatal AMI were
derived from the National Hospital Discharge Data Register. At
baseline, 113 men reported to have CHD, angina pectoris, coronary
bypass, or other coronary disease. Of the 910 men free from CHD at
baseline, a total of 109 subjects experienced a cardiac end point,
AMI, or CHD death during a mean follow-up of 10 years until year
2002.

Serum and Plasma Determinations

Venous blood samples were taken after fasting for 12 hours at
baseline (1991 to 1993). Lipoproteins were separated from fresh
serum samples by combination of ultracentrifugation and precipitation.10 Serum total, low-density lipoprotein (LDL) cholesterol, highdensity lipoprotein (HDL) cholesterol, and triglyceride concentrations were determined by enzymatic methods, and apolipoprotein B
(apoB) and apoA-I by immunoturbidimetry. The concentrations of
serum glutamyltransferase were measured by the kinetic method
following the recommendation of the European Committee for
Clinical Laboratory Standards. Concentrations of plasma fibrinogen
were determined based on clotting of diluted plasma with excess
thrombin by a coagulometer.
Serum IgG and IgA class antibodies to A. actinomycetemcomitans
and P. gingivalis were determined by multiserotype enzyme-linked
immunosorbent assay (ELISA) from serum samples stored at
20C.11 Two dilutions of each serum in duplicate were used and
the results (ELISA units [EU]) consisting of mean absorbances were
calculated as continuous variables. We included on each plate a high
and a low reference serum in duplicates to monitor the interassay
variations. The interassay coefficients for variation as calculated
from values of the low reference serum were 6.2% and 4.5% for A.
actinomycetemcomitans and 5.0% and 4.7% for P. gingivalis IgA
and IgG, respectively. A correction coefficient was calculated from
to the mean of the high reference values and the ELISA results of
each plate were normalized by this coefficient after the whole
material was analyzed. The subjects were considered seropositive for
A. actinomycetemcomitans and P. gingivalis when the corresponding
IgG value was 5.0 EU or the IgA value was 2.0 EU, which
represent the mean antibody levels plus 1.5SD of periodontally
healthy subjects.11 Combined antibody response in dentate subjects
was computed by summing IgG levels to A. actinomycetemcomitans
and P. gingivalis, and the value was considered high when it
exceeded 14.0 EU, which represents the corresponding mean antibody level of periodontally healthy subjects plus 3SD.5,11

Statistical Analyses
The significance of differences between cases and controls were
tested using t test or 2 test. The significance of differences between
IMT values in the tertiles of antibody levels was tested by t test.
Cumulative survival as well as the relative risks and their 95%
confidence intervals of cardiac end points in tertiles of A. actinomycetemcomitans and P. gingivalis antibody levels were estimated
using Cox regression models. Confounding factors included in the
model were age, smoking, plasma fibrinogen, diabetes, body mass
index, medication for hypertension, socioeconomic status, and serum
LDL and HDL cholesterol concentrations. The statistical analyses
were performed using SPSS program version 10.0 for Windows.

Figure 1. Mean IMT in the tertiles of antibody levels to periodontal pathogens. The mean carotid artery intima-media thickness was determined in the subjects free from CHD at baseline
(n907). The subjects were divided according to their dentate
status, and tertiles of IgA and IgG class antibody levels to periodontal pathogens A. actinomycetemcomitans (Aa) and P. gingivalis (Pg). The dentate subjects (n418) were also divided
according to the tertiles of combined antibody response (Aa
Pg), which is the IgG class antibody levels to A. actinomycetemcomitans P. gingivalis. The error bars indicate SEM. *P0.05,
**P0.01, and ***P0.001 compared with the first tertile using t
test.

Results
Both IgA and IgG antibody levels correlated positively with
mean IMT, especially among dentate subjects (n459): the
correlation coefficients (r) for mean IMT and A. actinomycetemcomitans IgA and IgG levels, and for P. gingivalis IgA
and IgG levels were 0.116 (P0.013), 0.097 (P0.038),
0.166 (P0.001), and 0.146 (P0.002), respectively. In all
subjects free from CHD at baseline (n907), mean IMT
increased in the tertiles of A. actinomycetemcomitans IgA (P
for trend 0.021), and P. gingivalis IgA (P0.001) and IgG
antibody levels (P0.023) (Figure 1). The same trend was
observed in the tertiles of combined antibody response in
dentate subjects free from CHD (n418) (P0.005) (Figure
1). The edentulous subjects (n481), who were free from
CHD at baseline, had higher mean IMT than the subjects with
natural teeth (Figure 1). The combined antibody response
correlated negatively with serum HDL cholesterol
(r0.073, P0.019) and positively with HDL triglyceride
concentration in the dentate population (r0.133, P0.004).
At baseline, a total of 113 men had already signs of CHD.
They were older (60.65.1 versus 55.76.6 years), had higher
serum cholesterol (5.611.08 versus 5.520.92 mmol/L), apoB
(1.040.28 versus 0.960.25 g/L), triglyceride (1.961.18
versus 1.571.01 mmol/L), and plasma fibrinogen (3.410.66
versus 3.130.56 g/L) concentrations, and lower serum HDL
cholesterol (1.000.29 versus 1.110.29 mmol/L) and apoA-I
(1.150.18 versus 1.210.18 g/L) concentrations than the men
free from CHD (n910), respectively (for all differences
P0.001). They also more frequently had diabetes (13.3%
versus 5.8%, P0.003) and hypertension (81.4% versus 22.0%,
P0.001), and were reported to more often have claudication
(22.1% versus 2.5%, P0.001) and history of any CVD in the
family (96.5% versus 84.5%, P0.001), respectively. The men
with CHD less often had their own teeth (34.8% versus 46.6%,
P0.019), and they were more often seropositive for P. gingivalis IgA (38.9% versus 28.5%, P0.021) and IgG (60.2%
versus 46.7%, P0.007) than the men free from CHD. Furthermore, the dentate subjects with CHD (n39) had more fre-

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Pussinen et al

Periodontal Antibodies and CHD

835

TABLE 1. Characteristics of Subjects Free From CHD at Baseline, With and

Without an End Point (AMI or CHD death) During the Follow-Up of 10 Years
Parameter

With an End Point

Without an End Point

P*

Mean (SD)
Age, y

57.4 (6.5)

55.4 (6.6)

0.003

BMI, kg/m2

28.1 (3.7)

27.4 (3.5)

NS

Waist-to-hip ratio

1.00 (0.04)

0.98 (0.04)

0.005

Alcohol/wk, g

89.2 (116.6)

79.4 (115.1)

NS

GGT, U/L

32.7 (26.8)

31.3 (39.2)

NS

S-chol, mmol/L

5.77 (0.86)

5.48 (0.92)

NS

S-apoB, g/L

1.05 (0.29)

0.95 (0.24)

0.001

S-HDL, mmol/L

1.07 (0.31)

1.11 (0.28)

NS

S-apoA-I, g/L

1.21 (0.19)

1.21 (0.18)

NS

S-TG, mmol/L

1.83 (1.30)

1.54 (0.96)

0.004

P-fibrinogen, g/L

3.29 (0.53)

3.11 (0.57)

0.001

Mean IMT, mm

0.94 (0.20)

0.86 (0.19)

0.001

Mean maximal IMT, mm

1.30 (0.30)

1.18 (0.27)

0.001

IgA, EU

2.02 (1.31)

1.77 (1.27)

NS

IgG, EU

3.70 (2.30)

3.49 (2.21)

NS

IgA, EU

1.89 (1.25)

1.82 (1.47)

NS

IgG, EU

6.18 (3.29)

5.74 (3.23)

NS

A. actinomycetemcomitans

P. gingivalis

N, %
N
Diabetic

109 (12.0)

801 (88.0)

11 (10.1)

42 (5.2)

0.043

Hypertensive

39 (35.8)

161 (20.1)

0.001

Smokers

38 (34.9)

208 (26.0)

0.050

Any CVD in family

98 (89.9)

671 (83.8)

NS

5 (4.6)

18 (2.2)

NS

50 (45.9)

370 (46.2)

NS

Claudication
Own teeth

*t test.
2 test.
CVD indicates cardiovascular disease; EU, ELISA units; GGT, glutamyltransferase; TG, triglycerides.

quently a high combined antibody response compared with the

dentate subjects without CHD (n420) (35.9% versus 18.8%,
P0.011).
During the mean follow-up of 10 years, 46 (40.7%) men
with a history of CHD at baseline experienced a secondary
coronary event, an AMI, or CHD death. Antibody levels to
periodontal pathogens were not associated with this coronary
event. However, the men who had a secondary event more
frequently wore dentures than the men who remained free
from a coronary event (76.1% versus 57.6%, P0.046; RR
for an end point 2.3, 95% CI, 1.02 to 5.40).
A total of 109 men free from CHD (n910) at baseline
experienced an AMI or CHD death during the follow-up time
of 10 years. The characteristics of these subjects with and
without an end point are summarized in Table 1. The subjects
with an end point were more frequently seropositive for A.
actinomycetemcomitans IgA than subjects without an end
point (15.5% versus 10.2%, P0.019). During the follow-up,
46 (5.1%) men with a high IgA class antibody level to A.

actinomycetemcomitans (third tertile) and 23 (2.5%) men

with a low antibody level (first tertile) experienced an end
point (P0.004 for difference) (Figure 2). The corresponding
rates for the second and first tertiles of P. gingivalis IgA class
antibody levels were 48 (5.3%) and 24 (2.6%), respectively
(P0.002 for difference) (Figure 2). The risk for CHD end
point increased with increasing tertiles of A. actinomycetemcomitans IgA antibody levels (Table 2). The multivariate RR
for the second tertile of P. gingivalis IgA antibody levels was
also significant (P0.004) compared with the first tertile, but
the association was not completely linear (P for trend 0.015).

Discussion
We found that elevated serum IgA class antibody levels to
periodontal pathogens, P. gingivalis and especially to A.
actinomycetemcomitans, were associated with CHD incidence in a population-based prospective study among men
free from CHD at baseline. The risk ratio for CHD was 2.0 to
2.1, which is of the same range as reported earlier for

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Arterioscler Thromb Vasc Biol.

April 2005

Figure 2. Cumulative survival rates for coronary events. The

men free from CHD at baseline were divided into tertiles
according to serum A. actinomycetemcomitans and P. gingivalis
IgA class antibody levels. The cumulative survival of AMI or cardiac death was analyzed by Cox regression model adjusted for
age, smoking, plasma fibrinogen, diabetes, hypertension, socioeconomic status, and serum LDL and HDL cholesterol
concentration.

clinically diagnosed periodontitis.3 In addition, edentulousness and seropositivity for P. gingivalis were associated with
prevalent CHD at baseline.
Both of these pathogens are connected to aggressive forms
of periodontal disease. A. actinomycetemcomitans occurs
particularly in periodontal diseases manifesting at young age

(younger than 35 years), but periodontitis caused by P.

gingivalis develops usually among middle-aged or elderly
people. Both A. actinomycetemcomitans and P. gingivalis
may also be found in low proportions among periodontally
healthy subjects and can therefore be considered part of the
endogenous oral flora. DNA of these pathogens has been
found in atherosclerotic plaques,12 and certain clones of A.
actinomycetemcomitans may exert potency to cause nonoral
infections.13
Periodontitis is accompanied by a strong immune response
to periodontal pathogens, which can be measured from saliva
and serum. Individual IgG class antibody levels are quite
stable over time and do not necessarily display activity or
severity of the disease; for example, periodontal treatment
decreases IgG class antibody levels only temporarily.14 The
cutoff level to seropositivity in our assay is relatively low
(mean antibody level plus 1.5SD of periodontally healthy
subjects) and validated using results from polymerase chain
reaction detection.11 Therefore, seropositivity indicates that
the individual is exposed to the pathogens, but that individual
may be in a state of carrier rather than with an active
disease. Another cutoff limit, which we have validated for our
assay, specifies individuals with a high combined antibody
response. Combining the IgG antibody levels of A. actinomycetemcomitans and P. gingivalis results in an assay with
sensitivity of 71% and specificity of 90% for finding periodontitis in dentate subjects.11 In the present population, the
percentage of subjects with serologically diagnosed periodontitis was 36% among men with CHD versus 19% among
men free from CHD. The proportions are in the same range as
in our earlier cross-sectional study conducted in 1997, in
which percentages were 38% and 27%, respectively.5 These
percentages are of the same magnitude as the earlier radiographically determined prevalence of severe periodontitis in
the Mini-Finland Oral Health Study (32%),15 suggesting that
the multiserotype ELISA may be a suitable method to
identify subjects with periodontitis in large-scale studies, in
which only serum samples are available.

TABLE 2. Relative risk for AMI and CHD Death in Tertiles of Serum Antibody
Levels for Periodontal Pathogens
Tertile
Antibody to

1st

2nd

3rd

P for Trend

1.0

1.2 (0.741.90)

1.3 (0.792.00)

0.616

Multivariate* 1.0

1.2 (0.721.86)

1.2 (0.761.94)

0.695

Univariate

1.0

1.8 (1.093.04)

2.2 (1.323.60)

0.009

Multivariate* 1.0

1.5 (0.912.58)

2.0 (1.213.33)

0.025

Univariate

A. actinomycetemcomitans
IgG
IgA

Univariate

P. gingivalis
IgG
IgA

1.0

1.6 (1.012.60)

1.5 (0.912.39)

0.120

Multivariate* 1.0

1.3 (0.792.08)

1.2 (0.701.88)

0.606

Univariate

1.0

2.2 (1.363.62)

1.8 (1.103.06)

0.006

Multivariate* 1.0

2.1 (1.263.37)

1.5 (0.872.47)

0.015

*Cox regression model adjusted for age, smoking, plasma fibrinogen, diabetes, medication for
hypertension, socioeconomic status, and serum LDLHDL cholesterol.
Relative risk for AMI and CHD death (95% CI).

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Pussinen et al
High IgA class antibody levels to periodontal pathogens in
saliva indicate persistent periodontitis with active tissue
destruction,14 whereas the significance of high IgA antibody
levels in serum is not fully understood. However, local and
systemic antibody levels correlate strongly with each other.
Therefore, our results suggest that prevalent CHD and future
risk of CHD are associated with active forms of periodontitis.
Persistently elevated antibodies belonging to IgA class also
appear to be one of the best serological markers of chronic
Chlamydia pneumoniae infection.16
The serum antibody levels to periodontal pathogens had a
moderate positive correlation with IMT at baseline, indicating
that exposure to periodontal pathogens may be related already
to subclinical atherosclerosis. In 3 earlier studies, carotid
artery plaque has been more common in subjects with severe
or moderate periodontitis,17 high P. gingivalis IgG titers,6 or
10 missing teeth.18 Edentulousness or missing teeth has
been found to be associated with CHD in several studies,5,19,20
and they can be considered as markers of past periodontal
disease.18 Also in the present study, the use of dentures was
associated with CHD, but it did not predispose to future
coronary events in CHD-free subjects. However, the mean
IMT was higher among the CHD-free men wearing dentures
than those without dentures. These observations imply that in
the final stage of periodontitis, when the teeth are already lost,
the damage is done regarding atherosclerosis. However,
denture-related mucosal lesions are also important determinants of CVD risk in edentulous subjects and associated with
elevated C-reactive protein concentrations.21 Furthermore,
edentulousness is strongly associated with low socioeconomic status and thereby also with other chronic infections,
which have been recognized as risk factors for CHD separately and as contributors to the infectious burden.22,23
Because chronic infections and CHD usually share common
etiopathogenic factors, eg, smoking and low socioeconomic
status, the nature of their association is difficult to explore in
humans.
The underlying mechanisms explaining the association
between periodontitis and increased risk for CHD are still
unclear. In periodontitis, the local inflammatory state and/or
the long-term systemic exposure to the pathogens or their
virulence factors act as triggers for systemic inflammation,
which can be detected as elevated concentrations of inflammation markers.3 This is supported by a recent study showing
that mice administered via oral and anal application with P.
gingivalis displayed local periodontal infection and exacerbated early atherosclerotic lesions.24 Furthermore, recent
studies on human subjects indicate that periodontitis increases the proatherogenic properties of LDL25 and decreases
the antiatherogenic properties of HDL in vitro,26 thereby
directing lipoprotein metabolism in an unfavorable direction.
Similarly, as in our earlier study,5 in the present study the
combined antibody response correlated inversely with serum
HDL cholesterol concentration. Furthermore, here the antibody response correlated directly with HDL triglyceride
concentration, which is the first to be affected by inflammation/infection.27,28 These observations suggest that periodontitis may interfere with HDL metabolism and thereby decrease proper removal of excess peripheral cholesterol.

Periodontal Antibodies and CHD

837

Recent studies on the role of periodontal pathogens in

atherosclerosis have concentrated on P. gingivalis. In addition to studies on animal models,24,29 31 cell culture studies
demonstrate that vesicles shed from the surface of P. gingivalis promote binding of LDL to macrophages, LDL modification, and macrophage-derived foam cell formation, a sign
of early atherosclerosis.32,33 Periodontitis is, however, a
multibacterial disease, and studies on the role of other
pathogens than P. gingivalis in CHD are scarce. To our
knowledge, the present study is the first to suggest that an
infection by A. actinomycetemcomitans may be associated
with the incidence of CHD. Consistent with our findings,
high serum levels of IgA antibodies to A. actinomycetemcomitans have been found to predispose to cerebrovascular
stroke in subjects free from CVD at baseline.34
Our study suggests that high IgA antibody levels to both P.
gingivalis and A. actinomycetemcomitans are associated with
CHD. These results also indicate that serum antibodies to
periodontal pathogens might be worth screening when mapping individual risk factors for CVD.

Acknowledgments
The Academy of Finland (grants 75953, 77613, and 211129), the
Paulo Foundation, and the Paavo Nurmi Foundation supported the
study financially by grants to P.J.P., and the Juho Vainio Foundation
by a grant to J.A.L. We thank the staff of the Research Institute of
Public Health, University of Kuopio, for data collection in the
Kuopio Ischemic Heart Disease Risk Factor Study (KIHD). The
KIHD study was supported by grants from the Academy of Finland
(grants 41471, 1041086, 2041022, and 45155) and the Ministry of
Education of Finland (grants 167/722/96, 157/722/97, 156/722/98)
to J.T.S., and the National Heart, Lung, and Blood Institute of the
USA (grant HL44199) to Professor George A. Kaplan.

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Serum Antibody Levels to Actinobacillus actinomycetemcomitans Predict the Risk for

Coronary Heart Disease
Pirkko J. Pussinen, Kristiina Nyyssnen, Georg Alfthan, Riitta Salonen, Jari A. Laukkanen and
Jukka T. Salonen
Arterioscler Thromb Vasc Biol. 2005;25:833-838; originally published online February 3, 2005;
doi: 10.1161/01.ATV.0000157982.69663.59
Arteriosclerosis, Thrombosis, and Vascular Biology is published by the American Heart Association, 7272
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