Periodontology 2000, Vol.
23, 2000, 110120
Printed in Denmark All rights reserved
Oral disease, cardiovascular
disease and systemic inflammation
J AMES D. B ECK, G ARY S LADE & S TEVEN O FFENBACHER
Atherosclerosis has been defined as a progressive
disease process that involves the large to medium
sized muscular and the large elastic arteries. Athero-
sclerosis can lead to coronary heart disease, as well
as myocardial and cerebral infarctions. Periodontitis
is an inflammatory reaction (to gram-negative, an-
aerobic bacterial infections) of the supportive tissues
surrounding the tooth, including the periodontal
ligament, cementum, and alveolar and supporting
bone.
World Health Organization statistics indicate that
in 1995, cardiovascular diseases were responsible for
20% of deaths worldwide, numbering 14 million
people. In developed countries, cardiovascular dis-
eases account for 50% of deaths and are the prin-
ciple cause of death, while in developing countries
it ranks third, accounting for 16% of deaths (34).
As shown in Table 1, heart disease is a major cause
of death in the United States. Overall, in 1995 heart
diseases ranked at the number one killer, accounting
for more than 2 million deaths and a death rate of
880 deaths per 100,000 people. However, the death
rates increase with age, rising to over 1800 deaths
per 100,000 in the 65 years and over age group (27).
These two diseases appear to have a number of
characteristics in common as they are more likely
Table 1. Rank, deaths and death rates due to
disease of the heart by age in 1995
Age group Rate per
(years) Rank Number 100,000 population
All 1 2,312,203
14 5 256
514 6 269
1524 5 964
2544 4 16,719
4564 2 101,975 199.3
65 1 627,844 1842.5
Source: National Center for Health Statistics (2).
110
Copyright C Munksgaard 2000
PERIODONTOLOGY 2000
ISSN 0906-6713
to occur in persons who are older, male, of lower
educational status, have fewer financial resources,
who smoke, are stressed, and are socially isolated.
These commonalties hint that periodontal diseases
and heart disease may share a similar causative
pathway.
Associations between periodontal
disease and atherosclerosis and
coronary heart disease
A number of studies in the 1990s have shown associ-
ations between oral conditions and atherosclerosis
and coronary heart disease. Other publications have
described and evaluated these associations in some
detail (2, 9, 17, 29), but they are summarized here
to provide a background from which to discuss the
possible mechanisms.
The findings from eight epidemiological studies
(three case-control and five prospective studies) are
presented in Table 2. Mattila et al. (20) conducted
two separate case-control studies that totaled 100
patients with acute myocardial infarction and 102
controls selected from the community at random.
Patients in the first series were 40 consecutive men
aged 50 years or less admitted because of acute myo-
cardial infarction and the controls were matched for
age, sex and neighborhood from the community and
invited for examination when the patient was admit-
ted. The second series consisted of 60 consecutive
cases, either men aged 60 years or less or women
880.0
aged 65 years or less. The dental examination was
1.6
performed while patients were in the hospital or
0.7
shortly thereafter. The dental index, which was used
2.7
in all of Mattilas publications, is the sum of scores
20.1
for the number of carious lesions, missing teeth,
probing depth measures (including pus in the
pocket), the number of periapical lesions and the
presence or absence of pericoronitis. These index
 Oral disease, cardiovascular disease and systemic inflammation

Table 2. Measure of association in epidemiological studies of periodontal disease and coronary heart
disease or stroke
Author/year Cases/controls Measure of association and
(reference) non-cases) Outcome Exposure 95% confidence interval
Case-control
Mattila 1989 (20) 100/102 Myocardial infarction Total Dental Index
Mattila 1993 (22) 100 Coronary atheromatosis Total Dental Index
Grau 1997 (10) 166/166 Stroke Total Dental Index
Prospective
Mattila 1995 (23) 52/(162) New myocardial infarction or Total Dental Index
death
DeStefano 1993 1786/(7974) Admits/death coronary heart Periodontal Index
(5) disease
Men 50
Joshipura 1996 New coronary heart disease Tooth loss due to
(14) periodontal disease
Beck 1996 (1) 203/(891) New coronary heart disease
58/(891) Fatal coronary heart disease
40/(911) Stroke
Genco 1997 (8) 68/(1304) New coronary heart disease Bone loss
---odds ratio; ---relative risk; ---incidence odds ratio; hazard ratio.

scores showed that patients had worse dental health
than controls in both studies. Logistic regression
analysis indicated that the association between poor
dental health and coronary heart disease persisted
after controlling for age, total cholesterol, high-den-
sity lipoprotein, triglycerides, C peptide, hyperten-
sion, presence of diabetes, and smoking.
A second article by Mattila et al. (22) reports on
associations between dental infections and athero-
sclerosis from a case control study (using the same
subjects as the earlier study). This second study was
limited to 100 subjects (88 men and 12 women) who
were referred for diagnostic coronary angiography.
The left main coronary artery, the a, b and c portions
of the right coronary artery, the circumflex artery,
and the left anterior descending artery were assessed
and graded for degree of occlusion on a five-point
scale. A semiquantitative estimate of atherosclerotic
mass was obtained by multiplying the scores of long
(5 mm) lesions by 2 and giving an additional score
of 1 to each segment with stenotic lesions in its pe-
ripheral branches. Coronary atheromatosis scores
were the sum of each of the components. These
scores were then divided into tertiles with the
highest tertile compared with the other two. The
dental index score was a combined score for dental
caries and periodontal infections. No significant as-
sociations between dental infections and coronary
atheromatosis was found for the 12 women. In a
multivariate analysis, significant associations were
found between dental infections, age, and triglycer-
ides and severe coronary atheromatosis for males.
These associations remained significant even though
total cholesterol, high-density lipoprotein chol-
esterol, smoking, hypertension, social class, and
body mass index were in the model and nonsignifi-
cant.
An article by Grau et al. (10) looking at the re-
lationship between infection and stroke does shed
some light on the Total Dental Index used by Mattila.
In their case-control study, Grau et al. found that the
Total Dental Index was independently associated
with cerebrovascular ischemia (odds ratio, 2.6; 95%
confidence interval, 1.18 to 5.7). However, they
found that only the periodontal components of the
Total Dental Index were responsible for this associ-
ation.
The first prospective study conducted by Mattila
et al. (23) is a 7-year follow-up of the cases from their
earlier study. They followed 182 men and 32 women
who had experienced a myocardial infarction in or-
der to determine new fatal and non-fatal coronary
events and overall mortality. The baseline dental
measures were the Total Dental Index (which in-
cluded caries, periodontitis, periapical lesions, and
pericoronitis) and the Pantomography Index (num-
ber of vertical bone pockets, furcations and peri-
apical lesions, and lesions caused by fourth-degree
caries or pericoronitis) used in Mattilas earlier
studies and recorded at the time of first admission
for a myocardial infarction. Cox proportional hazard
models were developed for the 52 patients who met

111
Beck et al.
the outcome criteria. The Total Dental Index (coef-
ficient0.18, SE0.06 was significant in a model that
included the Pantomography Index, the number of
previous infarctions, diabetes, body mass index, hy-
pertension, smoking, total cholesterol, high-density
lipoprotein cholesterol, triglycerides, socioeconomic
status, gender and age. Our conversion of the Cox
coefficients from the hazard models indicates that
the hazard ratio for the Total Dental Index was 1.2.
Thus, for each unit increase in the Total Dental Index
(range010), the hazard ratio for new coronary
event increased by a factor of 1.2.
DeStefano et al. (5) investigated coronary heart
disease and mortality based upon the first US Na-
tional Health and Nutrition Examination Survey,
which followed subjects for 14 years. This study
examined several potentially confounding variables
including age, gender, race, education, marital state,
systolic blood pressure, total cholesterol levels, body
mass index, diabetes, physical activity, alcohol con-
sumption, poverty index and cigarette smoking. De-
Stefano et al. demonstrated that, among the nearly
10,000 subjects analyzed, those with periodontitis
had a 25% increased risk of coronary heart disease
relative to those with minimal periodontal disease,
adjusted for the covariables mentioned above. In
men younger than 50 years of age, periodontal dis-
ease had an effect on coronary heart disease inci-
dence with a relative risk of 1.72.
Joshipura et al. (14) followed 44,119 men who
were health professionals (who had no reported
coronary heart disease symptoms at baseline, plaus-
ible dietary histories and no missing information on
age or number of teeth) for 6 years. All information
was obtained from mailed questionnaires. Analyses
were conducted for all study subjects and separately
for dentists, who comprised 58% of the subjects, and
the results were similar. The authors reported no as-
sociation between self-reported history of peri-
odontal disease with bone loss and coronary heart
disease with a relative risk of 1.04 (95% confidence
interval0.86, 1.25) when controlling for age, body
mass, exercise, smoking habits, alcohol consump-
tion, family history of myocardial infarction before
age 60 and vitamin E consumption. However, men
who had 010 teeth compared with men with 25 or
more teeth had a relative risk of 1.40 (95% confi-
dence interval1.04, 1.87). Stratification of tooth loss
by periodontal history showed that the association
was limited to men with periodontal disease. Among
6619 men with periodontal disease, the multivariate
relative risk was 1.67 (95% confidence interval1.03,
2.71) for men with 10 or fewer remaining teeth.
112
Beck et al. (1) conducted analyses on data from a
cohort study using combined data from the Norma-
tive Aging Study and the Dental Longitudinal Study
sponsored by the Department of Veterans Affairs.
The Normative Aging Study (3) is a longitudinal
study of male veterans in the Boston area, who re-
ceive their health care from community sources,
rather than VA facilities. The Dental Longitudinal
Study (15) was a substudy of the Normative Aging
Study begun 7 years later and included only men
who were systemically healthy at the time of the
dental examinations. Mean bone loss scores and
worst probing pocket depth scores per tooth were
measured on 1147 men during 19681971 and again
during a follow-up examination 18 years later. As
shown in Table 2, incidence odds ratios adjusted for
age and established cardiovascular risk factors were
1.5, 1.9, and 2.8 for bone loss and total coronary
heart disease, fatal coronary heart disease and
stroke, respectively.
When the degree or severity of the exposure is re-
lated to the incidence of the disease, we consider
this to be important information in establishing that
exposure as a cause. This dose-response effect or
biological gradient is important because, if a factor
is of causal importance, then the risk of developing
the disease should be related to the degree of ex-
posure to the factor.
The Beck et al. study (see above and reference 1)
reported the level of bone loss in relation to the
cumulative incidence of coronary heart disease, fatal
coronary heart disease and stroke respectively. For
all three outcomes, the point estimates and standard
errors show that increasing levels of bone loss at
baseline are accompanied by a higher cumulative
frequency of occurrence of disease 18 years later, in-
dicating a biological gradient between exposure and
occurrence of disease.
Genco et al. (8) investigated the association be-
tween periodontal infection and risk of cardiovascu-
lar disease in 1372 Native Americans of the Gila River
Indian Community, a group with a high prevalence
of diabetes mellitus. At baseline alveolar bone level
was assessed and cardiovascular status was moni-
tored for up to 10 years, using electrocardiograms.
New cardiovascular disease occurred in 68 people.
Among all age groups, bone level was predictive of
cardiovascular disease but did not remain significant
in a multivariate analysis. However, for persons 60
years bone level was predictive of cardiovascular dis-
ease, with an odds ratio of 2.68, (95% confidence in-
terval1.30, 5.5), adjusting for the effects of gender
and duration (10 years) of diabetes. Since this group
 Oral disease, cardiovascular disease and systemic inflammation

either did not smoke or had very low smoking levels,
the study indicates that the bone level cardiovascu-
lar disease association was not due to smoking, a risk
factor for both conditions.
In reviewing the evidence for oral conditions as
risk factors for heart disease, one is struck by the
consistency of the associations across studies that
used a variety of measures for both the exposure and
the outcome (Table 2). The strength of the associ-
ations are moderate, with most ranging from 1.2 to
1.5 and only the adjusted incidence odds ratios for
fatal heart disease and stroke in the Beck et al. study
were about 2.0, with the incidence odds ratios for
extent of probing depth greater than 40% and total
coronary heart disease approaching 3.0. Yet, a factor
associated with even 20% of the risk for coronary
heart disease would be associated with a very large
number of cases and is worthy of attention. It should
also be noted that all of these studies controlled for
relevant known risk factors for heart disease that
were available to the investigators (Table 3) but, as
in most studies, uncontrolled and residual con-
founding could still exist.
Associations between periodontitis
and cardiovascular, hematological
and rheological risk markers
In addition to studies that link periodontal disease
to cardiovascular outcomes, there is literature that
begins to indicate that periodontitis is also associ-
ated with changes in blood cellular and biochemical
composition that are secondary markers of cardio-
vascular risk, including rheological indicators of
hypercoagulation. Mattila et al. (27) conducted a
study on the relationship between dental infections
and several serum factors (factor VIII, factor VIII ris-
tocetin cofactor activity and von Willebrand factor).
They studied 40 consecutive patients with acute
myocardial infarction and 41 randomly selected con-
trols. All patients and controls were males aged 50
years and over. Blood samples for the assays were
taken for patients upon arrival at the hospital and at
1, 4, and 12 weeks and for controls at entry into the
study. Dental status was measured by the Total Den-
tal Index (described previously). These factors were
compared in persons with dental status scores below
and above the median Total Dental Index score. The
mean scores of all the factors were higher among pa-
tients and controls with poorer dental status than
among patients and controls with better dental sta-
tus, but only the von Willebrand factor scores were
statistically significant among controls (P0.02). In
a similar analysis using the dental Pantomography
Index, similar trends were found, but both factor VIII
ristocetin cofactor activity score (P0.01) and the
von Willebrand factor scores (P0.05) were signifi-
cantly higher among controls with poorer dental sta-
tus. While patient vs control differences were not re-
ported, it appears that there were no significant dif-
ferences between serum factor scores between
patients and controls, although the trends indicated
higher scores among patients than among controls.
Thus, relatively healthy controls with poor dental
status did have higher von Willebrand scores (a
marker of endothelial damage) than controls with
better dental status, but no differences were shown

Table 3. Degree of adjustment for associations between periodontal disease and coronary heart dis-
ease and stroke
Case-control studies Adjusted for
Mattila 1989 (20) High-density lipoprotein, smoking, hypertension, age, triglycerides, social class, diabetes,
total cholesterol and C peptide
Mattila 1993 (22) Age, triglycerides, high-density lipoprotein, smoking, hypertension, social class and body mass
index
Grau 1997 (10) Diabetes mellitus, pre-existing vascular diseases, social class and smoking
Prospective studies Adjusted for
Mattila 1995 (23) Smoking, hypertension, age, gender, triglycerides, social class, diabetes, serum lipids,
body mass index and previous myocardial infarctions
De Stefano 1993 (5) Age, gender, race, education, poverty, marital status, systolic blood pressure, cholesterol, diabetes,
body mass index, physical activity, alcohol and smoking
Joshipura 1996 (14) Age, body mass index, exercise, smoking, alcohol, vitamin E intake, family history of myocardial
infarction before age 60 years
Beck 1996 (1) Age, body mass index, total cholesterol, systolic blood pressure, diastolic blood pressure,
low-density lipoprotein cholesterol and smoking
Genco 1997 (8) Gender and duration of diabetes

113
Beck et al.
among patients who had just suffered an acute myo-
cardial infarction.
Kweider et al. (16) compared fibrinogen and white
cell count in patients with gingivitis or periodontitis
and in periodontally healthy controls. Fifty consecu-
tive gingivitis or periodontitis patients aged 2550
years attending the dental hospital and 50 individ-
uals with relatively healthy periodontal tissues (hos-
pital staff and patients) were evaluated using the
Plaque Index, Gingival Index, and the Community
Periodontal Index of Treatment Needs. Venus blood
was sampled for blind measurement of fibrinogen compared with controls (P0.001 for each). In ad-
and white cell count. Bivariate analyses showed that
periodontal patients had significantly higher fi-
brinogen (g/l) and white cell counts (109/l) than
controls (P0.001 for both). Multivariate analyses
showed an association between the gingival index
and both fibrinogen and white cell count. Each of
these associations was independent of age, smoking
status, social class, and group status (patient vs con-
trol). The Plaque Index and Community Periodontal
Index of Treatment Needs were reported to show
similar trends, but were not significant. In this study,
it appeared that individuals with poorer Gingival
Index scores had higher fibrinogen scores and white
cell counts, irrespective of whether they had been
classified as periodontal patients or controls.
Ebersole et al. (7) studied a group of 40 adult peri-
odontitis patients aged 3555 years both cross-sec-
tionally and longitudinally. These patients had no
uncontrolled medical conditions or abnormal blood
chemistries and no history of frequent periodontal
abscesses. The 35 controls used for the cross-sec-
tional part of the study were aged 3563 years, and
to be eligible for the study, they could only exhibit
Fig. 1. Proposed model. Source: Beck et al. (1). LPS:
lipopolysaccharide. PGE2: prostaglandin E2. IL-1b: in-
terleukin 1b. TNFa: tumor necrosis factor a. TxB2:
thromboxane B2.
114
mild to moderate gingivitis with no probing pocket
depths 4 mm and no radiographic evidence of al-
veolar bone loss. The purpose of the study was to
determine the relationship between periodontal sta-
tus and both C-reactive protein and haptoglobin
levels at baseline, to follow the C-reactive protein
and haptoglobin levels over time, and to assess any
changes in C-reactive protein and haptoglobin sub-
sequent to both local and then systemic periodontal
therapy. Each acute-phase reactant was significantly
increased in serum from adult periodontitis patients
dition, they found that C-reactive protein and hapto-
globin were significantly elevated in patients with
the most disease active sites over a 6-month period
(P0.02 and P0.001 respectively). Haptoglobin
levels declined after scaling and root planing
(P0.01) and after a 2-year administration of a non-
steroidal anti-inflammatory drug, significantly de-
creased haptoglobin levels were noted (P0.005). C-
reactive protein levels declined by 3540% after 12
years of treatment with the drug (P0.05).
Potential biological mechanisms
Infection has been recognized as a risk factor for
atherogenesis and thromboembolic events (5, 18, 20,
24, 28, 32). Gram-negative bacteria or the associated
lipopolysaccharide (endotoxin), when presented as
a systemic challenge in animal models, can induce
inflammatory cell infiltration into major blood ves-
sels, vascular smooth muscle proliferation and vas-
cular fatty degeneration and intravascular coagu-
lation. The remarkable similarities of bacterially in-
duced vascular pathology and the natural history of
atherogenesis has led certain investigators to suggest
that, in addition to genetic, lifestyle and dietary in-
fluences, infections of unknown origin may contrib-
ute to the observed cardiovascular pathology. The
chronic inflammatory burden of periodontal infec-
tion and the host response provide the basis for our
hypothetical model of the observed associations be-
tween periodontal disease and atherosclerosis, coro-
nary heart disease and stroke. This conceptual
model is presented in Fig. 1 and described more fully
in our 1996 article (1). Fundamentally, this model
emphasizes that among certain individuals there
may be an underlying hyperinflammatory trait in re-
sponse to stimuli that is manifest by an excessive
production of pro-inflammatory cytokines and lipid
mediators by monocytes and other cell types. This
hyperinflammatory trait (M) may be induced by

genetic, behavioral and environmental exposure and
may serve as a common antecedent to both cardio-
vascular and periodontal risk. However, in the pres-
ence of a pathogenic oral flora and resultant bactere-
mias and systemic inflammation, this may provide
an added burden to the host increasing the preva-
lence and severity of cardiovascular disease. Thus,
since coronary heart disease is a multifactorial dis-
ease process, we envision that periodontitis may
contribute to a certain fraction of cases, but that
many other factors can play an independent causa-
tive role in atherogenesis and infarctive disease.
Further details of this model that emphasize the ob-
ligate duality of both microbial exposure and in-
flammatory responses in the proposed linkage be-
tween periodontitis and coronary heart disease are
described elsewhere (1). In the present investigation
we sought to determine whether periodontitis was
associated with an acute phase response, as sug-
gested by the earlier by the report of Ebersole (7) and
as depicted on the right hand side of our working
model. To test this hypothesis we began by exam-
ining a nationwide database focussing on the acute-
phase response and C-reactive protein, specifically.
Recent evidence from United States
national survey data (NHANES III)
Methods
The third National Health and Nutrition Examina-
tion Survey (NHANES III) aimed to provide national
estimates of the health and nutritional status of the
United States civilian, noninstitutionalized popula-
tion aged 2 months and older. The survey was con-
ducted in two phases, from 19881991 and 1992
1994. Each phase, and the entire survey, provides na-
tional probability estimates for a broad range of self-
reported, examiner-assessed and laboratory-quan-
tified indicators of health and nutritional status. Full
documentation of the survey has been provided
elsewhere, and descriptive findings on oral health
status from the first phase have been reported (6). In
summary, the design of NHANES III was a complex,
multi-stage, stratified, clustered sample survey of the
civilian, noninstitutionalized population in the
United States. Sampled people were interviewed in
their homes and were invited to attend a mobile ex-
amination center for a standardized medical (includ-
ing dental) examination, physical measurements
and collection of biological samples. The periodontal
assessment included measurement of recession and
Oral disease, cardiovascular disease and systemic inflammation
probing pocket depth, both recorded in millimeters
using the National Institute of Dental Research
probe that has 2-mm colored bands. For these meas-
urements, all fractional millimeter measurements
were rounded down to the nearest whole millimeter.
Clinical attachment level was then calculated by the
computerized data entry system for all sites with
valid measurements of both recession and probing
pocket depth. Periodontal measurements were made
in two randomly selected quadrants (one quadrant
in the maxilla and one quadrant in the mandible) for
all teeth other than third molars, partially erupted
teeth or retained roots.
Blood samples were collected from persons aged 1
year or more using venipuncture in volumes varying
from 7 ml for children aged 13 years to over 100 ml
in some adults aged 2059 years. Serum was separ-
ated using standard laboratory techniques, and a
minimum volume of 0.3 ml was required for assess-
ment of C-reactive protein, which was quantified by
latex-enhanced nephelometry using a fully auto-
mated Behring Nephelometer Analyzer System (11).
In summary, diluted, centrifuged samples of serum
were mixed with latex particles coated with rabbit
antiC-reactive protein antibodies. An accelerator
reagent containing detergent was added to the reac-
tion mixture to enhance binding of the antigen-anti-
body complex. After 6 minutes, light scattering,
which is proportional to the concentration of the an-
alyte present in the sample, was measured by a
nephelometric procedure. An automatic blank sub-
traction was performed, and C-reactive protein con-
centrations in mg/dl were calculated with reference
to a calibration curve. Using this method, the mini-
mum detectable concentration of C-reactive protein
was 0.21 mg/dl. Repeat testing was done on all
samples with concentrations exceeding 1.0 mg/dl.
Some 39,695 people were selected for the two
phases of NHANES III, of whom 33,994 (86%) were
interviewed in their homes. All interviewed people
were invited to mobile examination centers for a
medical (including dental) examination and collec-
tion of biological samples, conducted within 4 weeks
of the interview. Seventy-eight percent (30,818) of
the selected people attended the mobile examina-
tion center. Some 28,059 people had dental exami-
nations although 8786 of them were excluded from
periodontal assessment because they were aged less
than 12 years, 1957 were excluded because they were
edentulous, 1165 were excluded because of medical
contraindications and 254 had no periodontal as-
sessment for unspecified reasons. Of the remaining
15,897 dentate people who had a periodontal exami-
115
Beck et al.
nation, C-reactive protein data were available for
14,979. This analysis was confined to the 12,949 of
these individuals who were aged 18 years or more.
Younger subjects were excluded in an attempt to ex-
clude false pockets, which were expected to distort
relationships between periodontal infection (as
measured by pocket depth) and systemic C-reactive
protein levels.
For this analysis, unit record data were obtained
from public-release CD-ROM ASCII files provided by
the National Center for Health Statistics. Data were
read from separate files containing interview data (to
obtain demographic and smoking history), dental
examinations and laboratory assays. Variables desig-
nating the sampling design and unit record weights
were obtained from the examination file. The sample
weights permit analysis to be generalized to the
United States population by correcting for: 1) differ-
ent probabilities of subject selection that were in-
herent in the sampling design; and 2) different levels
of nonresponse among sociodemographic groups.
For this analysis, the dependent variable was sys-
temic C-reactive protein level, which was used both
as a continuous variable and in three ordinal cate-
gories (0.21 mg/dl, which is below the detectable
threshold, 0.210.99 mg/dl and 1.0 mg/dl or more).
This highest category has been used as evidence of
clinically meaningful infection, as reported by Tracy
et al. (19, 33). When used as a continuous variable,
values below the detectable threshold were imputed
to 0.10 mg/dl approximately halfway between zero
and the 0.21 mg/dl threshold. The main exposure
variable was the extent of periodontal pocketing at
the 4 mm threshold as described by Carlos et al.
(4) Extent scores represent the percentage of probed
sites that have pocketing of at least 4 mm, and this
was categorized into three levels (0%, 110% and
10% of sites) to provide an ordinal indicator of ex-
posure to periodontal infection. Two additional co-
Table 4. NHANES III: percentage of sites with 4 mm of periodontal probing depth and C-reactive
protein measures in people aged 8 years
% of sites with No. of persons in
4 mm probing depths sample (unweighted)
0% 9145
19% 2253
10% 1550
Everyone 12,948
aa
Differs significantly from 0% severity group, P0.01.
bb
Differs significantly from 19% severity group, P0.01.
116
variates were assessed for potential confounding of
the periodontalC-reactive protein relationship: age
(seven categories) and self-reported smoking history
(never smoked, former smoker and current smoker).
Differences in mean C-reactive protein levels
among three groups defined by extent of periodontal
pocketing were evaluated using t-tests, both for cru-
de differences and after direct age standardization
among the three groups. The standard population
used was the United States population recorded at
the 1980 census and categorized into 10-year age
categories. Standardization was achieved using the
stdvar/stdwgt options in SUDAANs PROC
DESCRIPT (30). Stratified analyses were then con-
ducted among three categories of smoking. For the
analysis of three C-reactive protein categories, the
chi-square statistic was used to evaluate crude dif-
ferences in proportions among groups defined by
the extent of periodontal pocketing. Stratified analy-
ses, controlling for age and cigarette smoking, were
evaluated using the Mantel-Haenszel statistic. All
these analysis were conducted in SUDAAN using the
documented design and weight options specified in
the NHANES III documentation.
Results
Table 4 presents the relationship between the per-
cent of periodontal sites with a probing depth of 4
mm and C-reactive protein levels. Age-standardized
C-reactive protein levels are presented in two forms,
mean C-reactive protein, the percent of persons with
a clinically meaningful C-reactive protein level of 1
mg/dl. Both categorizations of C-reactive protein
values appeared to be related to the extent of sites
with probing depth of 4 mm. In fact, the mean
scores appeared to present a monotonic association.
People with 10% or more of their sites having a prob-
Age-standardized mean Age-standardized % of people
C-reactive protein with 1 mg/dl C-reactive
concentration (mg/dl) protein
Mean (SE) % (SE)
0.29 (0.01) 6.0 (0.37)
0.31 (0.02) 5.5 (0.69)
0.41 (0.04)aa,bb 12.5 (2.27)aa,bb
0.30 (0.01) 6.3 (0.36)
 Oral disease, cardiovascular disease and systemic inflammation

ing depth of 4 mm have significantly higher C-re-

active protein levels than those with no 4 mm
probing depths and those with 19% of their sites
having 4 mm probing depths. However, subjects in
the lowest two probing depth groups did not have
significantly different C-reactive protein levels.
Since smoking is known to be associated with
both periodontal disease and C-reactive protein
levels, associations between periodontal disease and
C-reactive protein, stratified by smoking status, are
presented in Table 5. Never smokers present essenti-
ally the same positive association between probing Fig. 2. NHANES III: age-specific C-reactive protein levels
and extent of probing depths of 4 mm for those who
depths of 4 mm and C-reactive protein levels that
have never smoked
were seen in Table 4. In former smokers, the highest
C-reactive protein levels appeared in those persons
with 19% of their sites with a probing depth of 4
mm. In current smokers the 10% group has signifi-
cantly higher C-reactive protein levels than the 19%
group, but they were not significantly greater than
those with no probing depths of 4 mm. Thus, C-
reactive protein levels appeared to be higher in non-
smokers with the greatest extent of probing depths,
but a current or past smoking history weakens the
periodontal diseaseC-reactive protein association.
On the other hand, the smoking-C-reactive protein
relationship only is evident for those with no prob-
ing depths 4 mm, indicating that the smoking-C-
reactive protein relationship may only be valid in
people without periodontal disease.
Fig. 2 and 3 represent age groupspecific associ- Fig. 3. NHANES III: age-specific C-reactive protein levels
ations between dichotomized probing depth extent and extent of probing depths of 4 mm for those who
currently smoke
scores and C-reactive protein levels for never
smokers and current smokers respectively. For never

Table 5. NHANES III: percentage of sites with 4 mm of periodontal probing depth and C-reactive
protein measures in people aged 18 years by smoking status
Age-standardized mean Age-standardized % of persons
C-reactive protein with 1 mg/dl C-reactive protein
concentration (mg/dl)
% of sites with No. of persons in
4 mm probing depths sample (unweighted) Mean (SE) Mean (SE)
Never smokers
0% 5089 0.28 (0.01) 5.4 (0.47)
19% 1092 0.27 (0.02) 4.5 (0.79)
10% 602 0.45 (0.06)aa, bb 14.0 (2.46)aa, bb
Former smokers
0% 1995 0.27 (0.02) 4.6 (0.66)
19% 482 0.40 (0.05)a 9.4 (3.49)
10% 368 0.34 (0.05) 5.2 (1.30)
Current smokers
0% 2061 0.36 (0.03) 9.1 (1.18)
19% 679 0.28 (0.03) 3.3 (0.74)a
10% 580 0.43 (0.06)b 16.0 (4.70)b
aa
Differs significantly from 0% severity group, P0.01.
bb
Differs significantly from 19% severity group, P0.01.
a
Differs significantly from 0% severity group, P0.05.
b
Differs significantly from 19% severity group, P0.05.

117
Beck et al.
smokers, it appeared that 1.0 mg/dl C-reactive pro-
tein levels were more frequent in people with prob-
ing depth scores 10% in all age groups and the
largest probing depth effects were seen in the age
groups 2534 and 5564 years old. For the current
smokers, the age-group specific pattern was mixed
with the age groups 3544 and 65 years, presenting
a negative association between periodontal disease
scores and C-reactive protein levels.
Discussion
During the 1990s, three case-control studies and five
longitudinal studies have consistently shown associ-
ations between periodontal status and coronary
heart disease or stroke. These associations, while
weak to moderate in strength, have been demon-
strated across diverse populations and appear to be
independent of traditional risk factors as measured
in these studies, and one study has demonstrated a
dose-response effect. Thus, clarifying the potential
mechanisms behind these associations is of great in-
terest. Since the earliest reported study by Mattila
(20), this periodontal diseasecoronary heart disease
association has been cited as evidence of the infec-
tion hypothesis; that infections are a major cause of
atherogenesis and thromboembolic processes. Infec-
tious diseases require both a pathogen and a suscep-
tible host, and the expression of that disease depend
both on the virulence of the pathogen and the im-
mune response of the host to that pathogen.
We presented a working model of the periodontal
diseaseatherosclerosis association (Fig. 1), which
hypothesizes that the presence of a M phenotype
places certain individuals at risk for both athero-
sclerosis and coronary heart disease and peri-
odontitis. Also, we suggest that certain factors, such
as diet, may exacerbate the hyperinflammatory
monocyte phenotype and may thereby contribute to
the morbidity of atherosclerosis and periodontal dis-
ease status. Furthermore, if a M individual con-
tracts periodontitis, the likelihood of atherogenesis
and thromboembolic events increases. Finally, peri-
odontal infections may directly contribute to the
pathogenesis of atherosclerosis and thrombo-
embolic events by providing repeated systemic vas-
cular challenges with the lipopolysaccharide, in-
flammatory cytokines and the microbes themselves.
In this report we provide further evidence that peri-
odontitis elicits a sufficient vascular challenge to
trigger a mild acute-phase response with an increase
in C-reactive protein levels, a marker of systemic in-
118
flammation. It should be pointed out, however, that
C-reactive protein is a nonspecific marker of the
acute-phase response. That is, many potential stim-
uli, including other infections, inflammatory con-
ditions and trauma may also account for mild in-
creases in C-reactive protein. However, in a com-
panion publication, we further report that the
potential effects of these other possible causes for C-
reactive protein elevation, such as arthritis and dia-
betes, do not appear to negate the effects of peri-
odontitis on increasing C-reactive protein levels (31).
Two recent articles by Ridker et al. (25, 26) add to
the accumulating evidence that inflammation may
be causally related to clinical cardiovascular disease.
In a nested case-control study of over 14,000 men
apparently healthy at baseline, moderately elevated
plasma concentrations of C-reactive protein (a
marker of inflammation) were associated with
greater risk of future myocardial infarction, stroke,
and symptomatic peripheral arterial disease. Aspirin
therapy was related to a reduction in coronary heart
disease events as well as reduced levels of C-reactive
protein. These findings imply that anti-inflamma-
tory agents may have preventive benefits for cardio-
vascular outcomes. Although the inflammatory stim-
uli responsible for the moderately increased C-reac-
tive protein levels could not be unequivocally
determined in the subjects studied by Ridker et al.,
the study by Ebersole (7) and the present investiga-
tion suggest that periodontal infections may be one
important stimulus for mildly elevated C-reactive
protein.
Finally, an increasing body of evidence suggests
that some periodontal microbes are capable of trig-
gering thromboembolic events. The potential sig-
nificance of oral gram-positive bacteria including
streptococcal species, such as Streptococcus sanguis,
in mediating thromboembolic events has been the
research focus of Herzberg et al. (13) and is pertinent
to our principal hypotheses. Systemic hematogenous
exposure to oral streptococcus has been recognized
as a potential initiator of bacterial endocarditis. Early
immunization experiments with oral streptococcal
organisms (especially Streptococcus mutans for vac-
cination against caries) resulted in the production
of autoimmune antivascular and anticardiac cross-
reactive immunoglobulins. Recently, landmark
studies by Herzberg et al. have identified the cross-
reactive immunodeterminants responsible (13). S.
sanguis contains an outer membraneassociated
protein with the 7-mer sequence Pro-Gly-Glu-Gln-
Gly-Pro-Lys, which is identical to the platelet-inter-
active domain of type I and type III collagens. This

bacterial protein thus presents or mimics the nor-
mal platelet receptor that initiates thrombus forma-
tion. Type III collagen is part of the wall and base-
ment membrane of vessels and is normally covered
with endothelial cells that mask these platelet bind-
ing receptor sequences from circulating blood cells.
Trauma or other noxious stimuli can expose these
receptors and thereby provide an important signal to
initiate hemostasis or thrombosis. Herzberg et al.
have repeatedly suggested the oral organisms such
as S. sanguis can present a similar thrombotic trig-
ger. Herzberg et al. also report that Porphyromonas
gingivalis (a gram-negative periodontal pathogen)
possesses properties similar to that of S. sanguis (13).
Finally, Haraszthy et al. (12) report that 19 of 27
atheromas obtained from patients during endart-
erectomy were positive for bacterial DNA from peri-
odontal pathogens. Of the 19, six were positive for
Actinobacillus actinomycetemcomitans, six for P. gin-
givalis, and seven for Prevotella intermedia. Taken
together, these findings suggest that periodontal
pathogens are found systemically and may serve as
a thromboembolic trigger.
In summary, it is our hypothesis that the presence
of a M phenotype places certain individuals at
risk for both cardiovascular disease and peri-
odontitis. Furthermore, we suggest that certain fac-
tors, such as diet or genetics, may exacerbate the
hyperinflammatory monocyte phenotype and there-
by contribute to the morbidity of atherosclerosis and
periodontal diseases. Thus, the M individual may
be at increased risk for developing atherosclerotic
disease (left side of Fig. 1), especially if other cardio-
vascular disease risk factors are present. If peri-
odontal pathogens are also present and periodontitis
results, the host response of the M individual is
likely to be unregulated (right side of Fig. 1). Thus,
periodontal infections may directly contribute to
atherogenesis and thromboembolic events by pro-
viding repeated systemic vascular challenges of pro-
inflammatory cytokines, periodontal pathogens, and
lipopolysaccharide. The pro-inflammatory cytokines
may be more closely associated with the more
chronic aspects of cardiovascular disease, such as
formation and progression of arterial plaques, while
the microbial and lipopolysaccharide exposures may
be associated with the more acute aspects of coro-
nary heart disease and stroke, such as thrombus for-
mation. Validating these possible mechanisms will
require considerable study in coming years, but
some early critical linkages between periodontitis
and cardiovascular disease appear to be gaining ad-
ditional confirmatory support with further study. In
Oral disease, cardiovascular disease and systemic inflammation
addition, the present demonstration that peri-
odontitis is a mild activator of the acute-phase re-
sponse is consistent with our earlier hypotheses that
periodontitis may elicit a systemic inflammatory re-
sponse. Since systemic hepatic, hematical and vas-
cular inflammation is a classic hallmark of cardio-
vascular disease, the possibility that periodontitis
may be one potential evoking stimulus for that sys-
temic inflammatory response bears further con-
sideration.
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