Periodontal Disease and Coronary Heart Disease
A Reappraisal of the Exposure
James D. Beck, PhD; Paul Eke, PhD, MPH, PhD; Gerardo Heiss, MD, MPH, PhD;
Phoebus Madianos, DDS, PhD; David Couper, PhD; Dongming Lin, MS; Kevin Moss, AS;
John Elter, DMD, PhD; Steven Offenbacher, DDS, PhD, MMSc
Background—Results from studies relating periodontal disease to cardiovascular disease have been mixed. Residual
confounding by smoking and use of clinical measures of periodontal disease rather than measures of infection have been
2 major criticisms. The aims of this study were to investigate relationships between prevalent coronary heart disease
(CHD) and 2 exposures, (1) clinical periodontal disease and (2) IgG antibodies to 17 oral organisms, and to evaluate
the role of smoking in these relationships.
Methods and Results—Our study is based on a subset of participants in the Atherosclerosis Risk in Communities (ARIC)
Study, who received a complete periodontal examination during visit 4 (1996–1998). The exposures were periodontal
status and serum IgG antibody levels against 17 periodontal organisms, and the outcome was prevalent CHD at visit 4.
Multivariable analyses indicate that periodontal status is not significantly associated with CHD in either ever smokers
or never smokers. Similar analyses evaluating antibodies indicate that high antibodies (above the median) to Treponema
denticola (odds ratio [OR]?1.7; 95% CI, 1.2 to 2.3), Prevotella intermedia (OR?1.5; 95% CI, 1.1 to 2.0),
Capnocytophaga ochracea (OR?1.5; 95% CI, 1.1 to 2.1), and Veillonella parvula (OR?1.7; 95% CI, 1.2 to 2.3) are
significantly associated with CHD among ever smokers, whereas Prevotella nigrescens (OR?1.7; 95% CI, 1.1 to 2.6),
Actinobacillus actinomycetemcomitans (OR?1.7; 95% CI, 1.2 to 2.7), and Capnocytophaga ochracea (OR?2.0; 95%
CI, 1.3 to 3.0) were associated with CHD among never smokers.
Conclusions—Clinical signs of periodontal disease were not associated with CHD, whereas systemic antibody response
was associated with CHD in ever smokers and never smokers. These findings indicate that the quality and quantity of
the host response to oral bacteria may be an exposure more relevant to systemic atherothrombotic coronary events than
clinical measures. (Circulation. 2005;112:19-24.)
Key Words: antibodies ? coronary disease ? epidemiology ? risk factors ? smoking
nism has been proposed whereby the burden of bacterial
pathogens, antigens, endotoxins, and inflammatory cytokines
of periodontitis contributes to the process of atherogenesis
and thromboembolic events. In response to infection and
inflammation, susceptible individuals may exhibit greater
expression of local and systemic mediators and may thereby
be at increased risk for a myocardial infarction or stroke.2
Case-control, cross-sectional, and longitudinal studies have
found that periodontitis is associated with coronary heart
disease (CHD) and cerebrovascular disease, even after adjust-
ment for a variety of potential confounders of these associa-
tions.3–26However, other studies have found either nonsig-
nificant positive trends or no association after adjustment for
variables considered to be confounders.27–31
eriodontitis is a chronic infection by oral bacteria that
affects the supporting structures of the teeth.1A mecha-
Concerns about the validity of the periodontitis–cardiovas-
cular disease associations have been expressed. A review by
Danesh32noted that studies were based on clinical measures
of periodontal disease and did not have direct measures of the
infection, such as bacterial counts or systemic antibody levels
to oral pathogens.
A second criticism focuses on the role of smoking, which
is a risk factor for both periodontal disease and heart disease
and must be considered as a confounder.33Most studies have
adjusted for smoking by means of multivariable analyses, an
approach open to bias due to residual confounding. As for
other morbidities, it has been suggested that statistical adjust-
ment is insufficient to control for smoking and that stratifi-
cation is needed.33In the present study we examined the
relationship between 2 types of periodontitis measures (clin-
ical and antibody) and prevalent CHD after stratification by
Received November 15, 2004; revision received February 24, 2005; accepted March 28, 2005.
From the Departments of Dental Ecology (J.D.B., K.M., J.E.), Epidemiology (G.H.), Biostatistics (D.C.), and Periodontology (D.L., S.O.), University
of North Carolina, Chapel Hill; Centers for Disease Control and Prevention, Division of Oral Health, Atlanta, Ga (P.E.); and University of Athens, Athens,
The online-only Data Supplement can be found with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.104.511998/DC1.
Correspondence to James D. Beck, PhD, Department of Dental Ecology, CB 7450, University of North Carolina, Chapel Hill, NC 27599. E-mail
© 2005 American Heart Association, Inc.
Circulation is available at http://www.circulationaha.orgDOI: 10.1161/CIRCULATIONAHA.104.511998
Coronary Heart Disease
smoking status and adjustment for other potential
The Atherosclerosis Risk in Communities (ARIC) Study is a
prospective investigation of the etiology and natural history of
atherosclerosis and of clinical cardiovascular disease in 4 US
communities.34A probability sample of 15 792 community-dwelling
residents aged 45 to 64 years at baseline took part in an evaluation
of cardiovascular risk factors and their sequelae. The ARIC clinical
examination included anthropometry including waist-to-hip ratio,
blood pressure, cognitive function, ECG, clinical chemistries,
plasma lipids, medications, and health questionnaires.35The Dental
ARIC, an ancillary study, was conducted at ARIC visit 4 during
1996–1998. Human subjects participated in the study after providing
informed consent to a protocol that was reviewed and approved by
the University of North Carolina School of Dentistry Committee on
Research Involving Human Subjects.
The cross-sectional Dental ARIC Study consisted of an oral
examination; collection of gingival crevicular fluid, dental plaque,
and serum; and interviews. Persons requiring antibiotic prophylaxis
for periodontal probing were excluded.
The outcome was prevalent, manifest CHD. The ARIC Study
collected self-reported physician-diagnosed CHD before enrollment
into the study (1987–1989) and abstracted hospital records for all
hospitalizations reported (yearly) by the cohort members followed by
validation of the discharge diagnoses according to standardized
criteria.36Unequivocal ECG signs of myocardial infarction during
any of the 3 examination visits that preceded the dental study were
also considered prevalent CHD at visit 4. Any events occurring
during visit 4 but after the dental examination were not included in
Two measures of periodontal exposures were used: clinical
periodontal disease and serum IgG antibody levels to 17 selected
periodontal organisms. Clinical measures included probing depth
and cementoenamel junction measures relative to the gingival
margin on 6 sites for all teeth. Clinical attachment level was
calculated from the sum of probing depth and cementoenamel
junction scores. Periodontal examiners at the ARIC centers were
calibrated to a standard examiner, and the percent agreement for
clinical attachment level within 1 mm between each examiner and
the standard examiner ranged from 83.2% to 90.2%. Weighted ?
statistics ranged from 0.76 to 0.86, indicating excellent agreement,
and intraclass correlation coefficients ranged from 0.76 to 0.90,
indicating excellent to outstanding agreement. Our case definition of
periodontal disease was independently derived during a meeting by
a Working Group on Surveillance Systems for Periodontal Infections
meeting. This 3-level definition is as follows: (1) severe periodon-
titis: ?2 interproximal sites (not on same tooth) with ?6-mm clinical
attachment level and ?1 interproximal site with probing depth
?5 mm; (2) initial periodontitis: ?2 interproximal sites with 4- or
5-mm clinical attachment level (not on same tooth) and no inter-
proximal sites with clinical attachment level ?6 mm; and (3)
healthy/gingivitis: individuals not meeting the above definitions.
IgG antibody levels to 17 oral organisms (Porphyromonas gingi-
valis, Prevotella intermedia, Prevotella nigrescens, Tannerella for-
sythensis [formerly Bacteroides forsythus], Treponema denticola,
Fusobacterium nucleatum, Actinobacillus actinomycetemcomitans,
Campylobacter rectus, Eikenella corrodens, Micromonas (Pep-
tostreptococcus) micros, Veillonella parvula, Capnocytophaga
ochracea, Seleomonas noxia, Actinomyces viscosus, Streptococcus
intermedius, Streptococcus sanguinis, and Streptococcus oralis)
represent the other exposure. Serum samples were frozen at ?80°C,
transported on dry ice to our laboratory, and stored in aliquots at
?80°C. The samples were assayed for IgG antibody levels directed
against the aforementioned periodontal organisms with the use of the
checkerboard immunoblotting technique described by Sakellari et
al.37See the online-only Data Supplement for additional details.
Periodontal organisms selected were representatives from clusters
of organisms reported to be associated with periodontal infections by
Socransky et al.38Absolute measures of systemic antibody to these
periodontal organisms were categorized into dichotomous variables
(high or low) with the median score for each organism used as the
cutpoint. The median value was used rather than the upper quartile
because stratification on smoking resulted in similar point estimates
of association but much wider CIs because of small cell sizes when
high antibody was defined as the highest quartile.
Participants were defined as never smokers, former smokers, or
current smokers by standardized interview. The former and current
categories were further divided into light or heavy smokers, with
light smokers reporting ?0 but ?20 pack-years of smoking and
heavy smokers reporting ?20 pack-years of smoking. This scheme
resulted in a 5-level categorization of smoking that simultaneously
takes into account both the intensity and the immediacy of smoking
exposure. This variable was used in multivariable models that were
not stratified by smoking status. For purposes of stratification, a
dichotomy of never smokers and ever (current and former) smokers
was used. Education was divided into basic (?12 years), intermedi-
ate (12 to 16 years), or advanced (17 to 21 years) and was included
to adjust for socioeconomic status. Age in years at visit 4 was
included, and a variable representing race/ethnicity (black or white)
and ARIC center was designed to control for the ethnic, regional, and
examiner differences in the ARIC cohort. A total of 49 individuals
who were not black or white or who were blacks seen in Minnesota
or Washington County, Md (n?49), were excluded because their
numbers were too small to be represented in the race/ethnicity/ARIC
center variable. See the online-only Data Supplement for additional
Statistical significance was set at 0.05, and the unit of analysis was
the person. Frequency distributions, means, empirical distribution
functions, and standard errors were determined to describe the data.
Bivariate relationships were assessed by t tests or Kolmogorov-
Smirnov tests for continuous variables and Cochran Mantel-
Haenszel ?2statistics and odds ratios (ORs) and 95% CIs for
categorical variables. Multivariable modeling was performed with
the use of binary logistic regression. Potential confounders were
based on the literature and our previous findings on the relationship
between clinical periodontal disease and CHD.13,39Covariates that
were significant main effects in the multivariable logistic regression
models (Tables 1 and 2) or that confounded the association between
antibodies and CHD by at least 5% were retained in the models. We
checked for multicollinearity among the 17 antibodies using the
collinearity diagnostics in SAS PROC REG. The antibody distribu-
tions were dichotomized at the median. The best score option in
PROC Logistic was used to identify the best single antibody model
and the best 2 antibodies model. In this procedure, the covariates
were forced into the model, and the antibodies were then eligible to
enter. The score option uses the branch and bound algorithm40to find
a specified number of models with the highest likelihood score (?2)
statistic for all possible model sizes, from 1-, 2-, and 3-effect models,
and so on, up to the single model containing all of the explanatory
effects. See the online-only Data Supplement for additional details.
Finally, the analyses of relationships between the 17 antibodies
and CHD by necessity involved multiple tests of significance. Hence,
type 1 error could exist. There are a number of methods to correct for
multiple testing, but we have opted for not adjusting the levels of
nominal statistical significance for multiple testing but to make
readers aware of the need to consider the statistical significance of
these associations with caution.
Of all ARIC cohort members examined at baseline (1987–
1989), 86.2% responded to a screening interview to deter-
mine eligibility for the oral examination. Of those screened,
15% were edentulous, and 17% were ineligible because they
had a medical contraindication to periodontal probing.
Among those eligible, 13% refused the dental examination. A
July 5, 2005
total of 11 656 ARIC participants were seen for visit 4, and
6793 underwent the periodontal examination. Individuals
who had missing or uncertain baseline CHD data (n?109)
also were excluded from the analysis. Finally, participants
missing serum samples reduced the number available for this
study to 5002. In several instances, checkerboards provided
unreadable antibody scores for 1 or 2 organisms. Thus, the
sample sizes for a few antibodies were ?5002, as shown in
Clinical periodontitis status was distributed as follows:
healthy/gingivitis, 42.3%; initial periodontitis, 40.8%; and
severe periodontitis, 16.9%. Associations between all study
variables and prevalent CHD appear in Table I of the
online-only Data Supplement. Although periodontal case
status was positively associated with CHD in bivariate
analyses, confounding of the association was evident after
adjustment for covariates that were either significant main
effects or confounders (Table 1). As a result, individuals with
initial periodontitis or severe periodontitis did not exhibit
significantly elevated odds of having CHD. Significant main
effects in this model were seen for age, male gender, heavy
current smokers, heavy former smokers, hypertension, HDL
cholesterol level (negative), LDL cholesterol level (negative),
and those who were not high school graduates. Additional
logistic models stratified on smoking (ever smokers and
never smokers) resulted in similar null findings.
At least 68% of the participants had a detectable antibody
level for each of the 17 organisms. At least 86% of partici-
pants had detectible antibody scores for P gingivalis, T
forsythensis, and T denticola, which are strongly associated
with chronic periodontitis. Antibodies to P intermedia, M
micros, P nigrescens, and A actinomycetemcomitans were
detected in ?90% of the individuals, and V parvula was least
likely to be detected at 68.6% (data not shown; see online-
only Data Supplement). Significant unadjusted associations
were seen between high antibody level (median or above)
against all organisms except S sanguinis, S intermedius, and
A viscosus and prevalent CHD. The strongest associations
were seen for M micros (OR?1.7; 95% CI, 1.3 to 2.1) and C
ochracea (OR?1.8; 95% CI, 1.4 to 2.8). The lower confi-
dence limits for a number of the significant antibodies were
close to 1.0. Evaluation of multicollinearity among the 17
antibodies resulted in a condition index of 8.7, indicating
collinearity levels that were not troublesome.
Because there were a number of significant unadjusted
associations between high antibodies and CHD, we further
evaluated antibody-CHD associations by means of a series of
logistic regression models adjusting for covariates that were
either significant main effects in the model or that con-
founded the antibody-CHD association by at least 5%. In
addition, we stratified the participants according to whether
or not they had ever smoked (Table 2). The antibody-CHD
patterns for ever smokers and never smokers appear to differ.
Clinical Periodontal Status and Prevalent CHD (n?4846)
Multivariable Logistic Model for Association Between
Variables in Model OR95% CI
Age at visit 4 (5-year intervals)
Gender (female?0, male?1)
Race/center (reference: Jackson blacks)
North Carolina whites
North Carolina blacks
Washington County, Md, whites
Smoking status (reference: never smoker)
Diabetes (no?0, yes?1)
Hypertension (no?0, yes?1)
Waist-to-hip ratio (Z score)
HDL cholesterol level (mg/dL, SD)
LDL cholesterol Level (mg/dL, SD)
?17 y (referent)
? ? ?
? ? ?
? ? ?
? ? ?
Bold type indicates that CI does not include 1.0.
Models* of Associations Between High† Antibody Level to
Various Oral Organisms and Prevalent CHD Stratified by
Summary of Multivariable Logistic Regression
High Antibody to
OR (95% CI)
OR (95% CI)
1.7 (1.2- 2.7)
Bold type indicates that CI does not include 1.0.
*ORs and 95% CIs are adjusted for age, sex, race/center, diabetes,
hypertension, waist-to-hip ratio, HDL, LDL, and education (3 levels). Ever
smokers are also adjusted for pack-years of smoking.
†High antibody indicates that IgG level is above median for each organism.
Beck et alPeriodontitis and CHD: Reappraisal of the Exposure
Antibody to T denticola, which with P gingivalis and T
forsynthesis is strongly associated with chronic periodontitis,
was significantly related to CHD in smokers, whereas none of
those antibodies were significant in never smokers. However,
there is a positive trend, and the ORs are similar to those in
ever smokers. In ever smokers, antibody to P intermedia was
significantly related to CHD (OR?1.5), and high antibodies
to C ochracea and V parvula were associated with CHD
(ORs?1.5 and 1.7, respectively). Among never smokers,
antibody to P nigrescens was associated with CHD. In
addition, high antibodies to A actinomycetemcomitans and C
ochracea were related to prevalent CHD. Because space
limits presentation of the 34 full models, significant main
effects among the covariates in the ever smokers were age
(5-year increments), gender (male), hypertension (yes), and
pack-years of smoking, and both HDL and LDL cholesterol
were negatively associated with CHD. For never smokers,
significant main effects were age (5-year increments), gender
(male), diabetes (yes), and hypertension (yes), and both HDL
and LDL cholesterol were negatively associated with CHD.
Analyses of antibodies as log-transformed, continuous vari-
ables produced patterns similar to those of antibodies dichot-
omized at the median (not shown). For example, all 3
antibodies significant in Table 2 for never smokers also were
significant as continuous variables plus P intermedia. For
ever smokers, antibodies to M micros, F nucleatum, S noxia,
C ocracea, and V parvula were significant.
Analyses of the relationship between the presence of
multiple high antibody titers to oral organisms and CHD with
the use of the best score option in logistic regression and with
adjustment for all covariates revealed that the best-fitting
2-variable antibody model for ever smokers was a combina-
tion of T denticola and V parvula (not shown). Individuals
with high antibody levels to both T denticola and V parvula
have a CHD prevalence of 11.0% compared with a preva-
lence of 5.3% for individuals with low antibodies to both
organisms (OR?2.0; 95% CI, 1.4 to 2.9). The best-fitting
model for a combination of 2 antibody titers and CHD in
never smokers included P nigrescens and C ochracea. Indi-
viduals with high antibody levels to both P nigrescens and C
ocracea have a CHD prevalence of 6.6% compared with a
prevalence of 2.6% for individuals with low antibodies to
both organisms (OR?2.3; 95% CI, 1.4 to 4.0).
Study findings indicate that our a priori clinical case defini-
tion of periodontitis was not significantly associated with an
increased prevalence of CHD after adjustment for a number of
CHD risk factors. This is consistent with other studies.27–29,31
Studies reporting on this association have used a variety of
definitions of periodontal disease as an exposure, and our own
work has used ?1 definition. Because there is almost no
information on which clinical periodontal measures and their
severity may be related to systemic conditions, the range of
exposures reported in the literature may be one reason for the
inconsistency in findings. Our study obtained detailed clinical
periodontal measures, meaning that we could explore a variety
of clinical definitions as they may relate to CHD, which we did.
A strength of this study is that we used a clinical definition that
was independently derived by a group interested in surveillance
of periodontal disease in the United States. Interestingly, the
prevalence of severe periodontitis as defined in this study was
?16%, which is similar to national estimates for this condition.
However, this definition and others that we have previously
published (and some that we have not published) were not
associated with prevalent CHD, and we are persuaded that such
an association does not exist in this study population.
In earlier publications we reviewed evidence indicating
that the chronic inflammatory burden of periodontal infection
and the host response provide the basis for the observed
associations between periodontal disease and atherosclerosis
and CHD.8,41The results of this study lend support to our
original working model, and they support and extend the
findings of Pussinen et al,16who found associations between
elevated A actinomycetemcomitans and P gingivalis antibody
titers and CHD, after adjusting for age and several CHD risk
factors. Support for our findings also comes from studies that
indicate that several periodontal organisms, including P
gingivalis, T denticola, S sanguinis, and A actinomycetem-
comitans, have been detected directly within the atheroscle-
rotic plaque lesion of the vessel wall.42,43Furthermore,
periodontal organisms such as P gingivalis have been re-
ported to invade human coronary artery cells and induce
several pathological responses,44and long-term systemic
challenge with P gingivalis was reported to accelerate athero-
genic plaque progression.45
We are aware of uncertainties in the interpretation of high
antibody titers to oral organisms in relation to periodontal
disease. The antibody response varies between individuals,
and immune system response to an organism can be influ-
enced by the individual’s genetic and immunological back-
ground, previous exposure to the organisms, and the dose,
timing, route, and immunogenic characteristics of the anti-
genic challenge. Systemic exposures that originate from local
infection may imply an insufficient local response to prevent
systemic entry, as well as factors that promote acute episodes
of periodontal disease activity, such as smoking.46The
immune response to infection may also undergo age-related
changes that result in loss of response and functional capac-
ity.47Hence, we controlled for age and stratified on smoking
High antibody titers could represent a response to an active
phase of infection in subjects with periodontitis but could also
reflect a host response to an oral pathogen that confers
protection to an individual without periodontal disease. The
premise for this study was the assumption that an antibody
response merely indicates systemic exposure to an oral
organism. The distribution of periodontopathic organisms in
gingival plaque is closely related to antibody levels to the
intact bacteria in serum. For example, studies have shown a
direct relationship between the serum anti–P gingivalis IgG
levels and subgingival colonization by P gingivalis48consis-
tent with a systemic antibody response as a reflection of the
host response to infections by periodontal organisms. In-
creases in systemic antibody response to organisms have also
been associated with episodes of periodontal disease activity.
Longitudinal studies have shown that elevation in systemic
antibody specificities to periodontal organisms is an indicator
July 5, 2005
of periodontal disease recurrence,49although it is not a
sensitive marker for initial periodontitis.50High antibody
titers to T forsythensis have also been reported to be signif-
icantly higher in periodontitis patients.51Finally, although the
role of antibodies to periodontal organisms in host immune
protection against infections by periodontal organisms is not
fully elucidated, it appears that antibody level is not a good
quantitative indicator for periodontal disease. Nonetheless,
antibody to periodontopathic organisms appears to be a
reliable index measure for systemic exposure to these organ-
isms. Thus, we conservatively interpret the results of this
study to indicate that systemic exposure to oral organisms is
related to the prevalence of detected CHD.
Although the cross-sectional design allowed us to examine
associations between multiple periodontal organisms and
carotid atherosclerosis, no inference can be made about the
antecedent-consequent nature of our results. Similarly, al-
though serum antibody levels are stable over some time, it is
unknown whether in our study population high levels of
antibody to periodontal organisms are the result of incident,
prior, or active reinfection. Thus, the temporal relationship
between exposure to periodontal organisms and a cardiovas-
cular event cannot be addressed. Misclassification of event
status can be expected to be minimal because disease status
was defined and determined by standardized protocols and
procedures were established by the ARIC Study and verified
over the 9 years before the dental examination. Standardized
and controlled protocols were also used in ARIC to obtain
measures for the covariates included in our analyses. Al-
though the validity of serum antibody measures for periodon-
tal organisms could be influenced by cross-reactivity to other
antigenic-related species from nonoral sites, we know of no
basis to suspect differential misclassification between cases
and control for this reason, and we determined very weak
correlations between antibody measures for the most anti-
genically related species (eg, between Streptococcus species)
and a low percentage of concordance between high antibody
levels to these closely related organisms in our study popu-
lation. It may appear counterintuitive, but it is not unusual in
cross-sectional studies that LDL cholesterol was negatively
associated with prevalent CHD. Additional analyses (not
shown) indicated that more than half of the individuals with
prevalent CHD were taking cholesterol-lowering medica-
tions, which may account for the direction of the association.
The analyses of relationships between the 17 antibodies
and CHD by necessity involved multiple tests of significance.
Hence, type 1 error could exist. For example, Table 2 is a
summary of 34 logistic regression models that resulted in 9
significant associations. With a significance level of 0.05, 1
or 2 significant associations can be expected by chance alone.
We have opted for not adjusting the levels of nominal
statistical significance for multiple testing but to make read-
ers aware of the need to consider the statistical significance of
these associations with considerable caution.
In this study population, the clinical signs of periodontal
disease were not associated with CHD, whereas an indicator
of systemic exposure to oral organisms (high antibody levels)
was associated with prevalent CHD in current and former
smokers as well as never smokers. Systemic exposure to ?1
oral organism was related to a higher prevalence of CHD,
especially in never smokers. These findings suggest that the
quality and quantity of an individual’s host response to oral
pathogens, which results in clinical expression of periodontal
disease, may also be a more direct measure of periodontal
disease as an exposure for CHD. Consequently, we believe
that these findings are relevant for future research in that they
indicate that clinical measures of periodontitis may not
adequately represent the systemic burden of periodontal
disease. Instead, future researchers may want to use measures
that better capture the interplay of the infection, the host
immune and inflammatory responses, and resulting clinical
signs of this complex exposure that may affect general health.
The ARIC Study is performed as a collaborative study supported by
National Heart, Lung, and Blood Institute contracts N01-HC-55015,
N01-HC-55016, N01-HC-55018, N01-HC-55019, N01-HC-55020,
N01-HC-55021, and N01-HC-55022 and grant R01-DE11551 from
the National Institute of Dental and Craniofacial Research. The
authors thank the staff and participants of the ARIC Study for their
Dr Beck is principal investigator of the grant producing the data.
Kevin Moss is on the research grant. Drs Offenbacher and Couper
are coinvestigators on the grant and Dr Heiss is an investigator on the
parent ARIC study.
1. Offenbacher S. Periodontal diseases: pathogenesis. Ann Periodontol.
2. Beck J, Offenbacher S, Williams RR, Gibbs P, Garcia R. Periodontitis: a
risk factor for coronary heart disease? Ann Periodontol. 1998;3:127–141.
3. Syrajanen J, Peltola J, Valtonen V, Iivanainen M, Kaste M, Huttunen J.
Dental infections in association with cerebral infarction in young and
middle-aged men. J Intern Med. 1989;225:179–184.
4. Paunio K, Impivaara O, Tiesko J, Maki J. Missing teeth and ischemic
heart disease in men aged 45–64 years. Eur Heart J. 1993;14:54–56.
5. Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, Kesaniemi YA,
Syrjala SL, Jungell PS, Isoluoma M, Hietaniemi K, Jokinen MJ. Asso-
ciation between dental health and acute myocardial infarction. BMJ.
6. Mattila K, Rasi V, Nieminen M, Valtonen V, Kesaniemi A, Syrjala S,
Jungell P, Huttunen JK. von Willebrand factor antigen and dental
infections. Thromb Res. 1989;56:325–329.
7. Mattila KJ, Valle MS, Nieminen MS, Valtonen VV, Hietaniemi KL.
Dental infections and coronary atherosclerosis. Atherosclerosis. 1993;
8. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. Periodontal
disease and cardiovascular disease. J Periodontol. 1996;67:1123–1137.
9. Grau AJ, Buggle F, Siegler C. Association between acute cerebrovascular
ischemia and chronic and recurrent infection. Stroke. 1997;28:
10. Arbes SJ, Slade GD, Beck J. Association between extent of periodontal
attachment loss and self-reported history of heart attack: an analysis of
NHANES III data. J Dent Res. 1999;78:1777–1782.
11. Loesche W, Schork A, Terpenning M, Chen Y, Kerr C, Dominguez B.
The relationship between dental disease and cerebral vascular accident in
elderly United States veterans. Annal Periodontol. 1998;3:161–174.
12. Beck J, Elter J, Heiss G, Couper D, Mauriello S, Offenbacher S. Rela-
tionship of periodontal disease to carotid artery intimal-media wall
thickness: the Atherosclerosis Risk in Communities (ARIC) Study. Arte-
rioscler Thromb Vasc Biol. 2001;21:1816–1822.
13. Slade GD, Ghezzi EM, Heiss G, Beck J, Riche E, Offenbacher S.
Relationship between periodontal disease and C-reactive protein among
adults in the Atherosclerosis Risk in Communities Study. Arch Intern
Beck et alPeriodontitis and CHD: Reappraisal of the Exposure
14. Emingil G, Buduneli E, Aliyev A, Akilli A, Atilla G. Association between
periodontal disease and acute myocardial infarction. J Periodontol. 2000;
15. Desvarieux M, Demmer R, Rundek T, Boden-Albala B, Jacobs D Jr,
Papapanou PN, Sacco R. Relationship between periodontal disease, tooth
loss, and carotid artery plaque: the Oral Infections and Vascular Disease
Epidemiology Study (INVEST). Stroke. 2003;34:2120–2125.
16. Pussinen P, Jousilahti P, Alfthan G, Palosuo T, Asikainen S, Salomaa V.
Antibodies to periodontal pathogens are associated with coronary heart
disease. Arterioscler Throm Vasc Biol. 2003;23:1250–1254.
17. Joshipura K, Hung H, Rimm EB, Willett WC, Ascherio A. Periodontal
disease, tooth loss, and incidence of ischemic stroke. Stroke. 2003;34:
18. Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke T, Vita J. Peri-
odontal disease is associated with brachial artery endothelial dysfunction
and systemic inflammation. Arterioscler Throm Vasc Biol. 2003;23:
19. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell CM. Dental
disease and risk of coronary heart disease and mortality. BMJ. 1993;306:
20. Hung H, Willett WC, Merchant A, Rosner B, Ascherio A, Joshipura K.
Oral health and peripheral arterial disease. Circulation. 2002;107:
21. Mattila KJ, Valtonen VV, Nieminen M, Huttunen JK. Dental infection
and the risk of new coronary events: prospective study of patients with
documented coronary artery disease. Clin Infect Dis. 1995;20:588–592.
22. Mendez MV, Scott T, LaMorte W, Vokonas P, Menzoian JO, Garcia R.
An association between periodontal disease and peripheral vascular
disease. Am J Surg. 1998;176:153–157.
23. Morrison H, Ellison L, Taylor G. Periodontal disease and risk of fatal
coronary heart and cerebrovascular disease. J Cardiovasc Risk. 1999;
24. Jansson L, Lavstedt S, Frithiof L, Theobald H. Relationship between oral
health and mortality in cardiovascular diseases. J Clin Periodontol. 2001;
25. Ajawani S, Mattila K, Narhi T, Tilvis R, Ainamo A. Oral health status,
C-reactive protein and mortality: a ten year follow-up study. Gerodon-
26. Elter JR, Offenbacher S, Toole JF, Beck JD. Relationship of periodontal
disease and edentulism to stroke/TIA. J Dent Res. 2003;82:998–1001.
27. Joshipura KJ, Rimm EB, Douglass CW, Trichopoulos D, Ascherio A,
Willett WC. Poor oral health and coronary heart disease. J Dent Res.
28. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Christen WG. Peri-
odontal disease and risk of subsequent cardiovascular disease in U.S.
male physicians. J Am Coll Cardiol. 2001;37:445–450.
29. Hujoel P, Drangsholt M, Spiekerman C, DeRouen T. Periodontal disease
and coronary heart disease risk. JAMA. 2000;284:1406–1410.
30. Hujoel P, Drangsholt M, Spiekerman C, DeRouen T. Examining the link
between coronary heart disease and the elimination of chronic dental
infections. J Am Dent Assoc. 2001;132:883–889.
31. Hujoel P, Drangsholt M, Spiekerman C, DeRouen T. Pre-existing car-
diovascular disease and periodontitis: a follow-up study. J Dent Res.
32. Danesh J. Coronary heart disease, Helicobacter pylori, dental disease,
Chlamydia pneumoniae, and cytomegalovirus. Am Heart J. 1999;138:
33. Hujoel P, Drangsholt M, Spiekerman C, DeRouen T. Periodontitis:
systemic disease associations in the presence of smoking: causal or
coincidental? Periodontol 2000. 2002;30:51–60.
34. Heiss G. Atherosclerosis Risk in Communities: a follow-up study of early
arterial lesions in the general population. In: Glagov S, ed. Pathology of
Human Atherosclerotic Plaque. New York, NY: Springer-Verlag; 1989:
35. The ARIC Investigators. The Atherosclerosis Risk in Communities
(ARIC) Study: design and objectives. Am J Epidemiol. 1989;129:
36. Rosamond WD, Chambless LE, Folsom AR, Cooper LS, Conwill DE,
Clegg L, Wang CH, Heiss G. Trends in the incidence of myocardial
infarction and in mortality due to coronary heart disease, 1987 to 1994.
N Engl J Med. 1998;339:861–867.
37. Sakellari D, Socransky S, Dibart S, Taubman M. Estimation of serum
antibody to subgingival species using checkerboard immunoblotting.
Oral Microbiol Immunol. 1997;12:303–310.
38. Socransky S, Haffajee A, Cugin M, Smith C, Kent R. Microbial com-
plexes in subgingival plaque. J Clin Periodontol. 1998;25:134–144.
39. Beck J, Offenbacher S. Oral health and systemic disease: periodontitis
and cardiovascular disease. J Dent Educ. 1998;62:859–870.
40. Furnival G, Wilson R. Regression by leaps and bounds. Technometrics.
41. Offenbacher S, Madianos PN, Champagne C, Southerland JH, Paquette
D, Williams R, Slade GD, Beck J. Periodontitis-atherosclerosis syn-
drome: an expanded model of pathogenesis. J Periodontal Res. 1999;34:
42. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ. Identification
of periodontal pathogens in atheromatous plaques. J Periodontol. 2000;
43. Okuda K, Ishihara K, Nakagawa T, Hirayama A, Inayama Y. Detection
of Treponema denticola in atherosclerotic lesions. J Clin Microbiol.
44. Dorn B, Dunn WJ, Progulske-Fox A. Invasion of human coronary artery
cells by periodontal pathogens. Infect Immun. 1999;67:5792–5798.
45. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonas
gingivalis infection accelerates the progression of atherosclerosis in a
heterozygous apolipoprotein E–deficient murine model. Circulation.
46. Califano J, Schifferle R, Gunsolley J, Best A, Schenkein HA, Tew J.
Antibody reactive with Porphyromonas gingivalis serotypes K1–6 in
adults and generalized early-onset periodontitis. J Periodontol. 1999;70:
47. Papapanou PN, Neiderud A, Papadimitriou A, Sandros J, Dahlen G.
“Checkerboard” assessments of periodontal microbiota and serum
antibody responses: a case-control study. J Periodontal. 2000;71:
48. Kojima T, Yano K, Ishikawa I. Relationships between serum antibody
levels and subgingival colonization of Porphyromonas gingivalis in
patients with various types of periodontitis. J Periodontol. 1997;68:
49. Ebersole JL, Cappelli D, Stewen MJ, Willmann DE, O’Dell DS. Host
response assessment in recurring periodontitis. J Clin Periodontol. 1996;
50. Tanner AC, Kent RL Jr, Maiden MF, Macuch PJ, Taubman MA. Serum
IgG reactivity to subgingival bacteria in initial periodontitis, gingivitis
and healthy subjects. J Clin Periodontol. 2000;27:473–480.
51. Persson G, Schlegal-Bregenzer B, Chung W, Huston L, Oswald T, Robert
M. Serum antibody titers to Bacteroides forsythus in elderly subjects with
gingivitis and periodontitis. J Clin Periodontol. 2000;27:839–845.
July 5, 2005