Periodontology 2000, Vol. 44, 2007, 113–126
Printed in Singapore. All rights reserved
Cardiovascular disease,
inflammation, and periodontal
infection
D A V I D W. P A Q U E T T E , N A D I N E B R O D A L A & T I M O T H Y C. N I C H O L S
Cardiovascular and periodontal diseases are common
inflammatory conditions in the human population.
In atherogenesis, inflammation plays a continuous
role from endothelial cell expression of adhesion
molecules to the development of the fatty streak,
established plaque, and finally plaque rupture.
Exposures to infections like periodontal disease have
been postulated to perpetuate inflammatory events
in atherogenesis. Recent observational studies and
meta-analyses continue to demonstrate a modest but
statistically significant increased risk for cardiovas-
cular disease among persons exposed to periodontal
disease or infection. Experiments with animal models
further indicate that periodontal infection can in-
crease atherosclerosis in the presence or absence of
hypercholesterolemia. While the available pilot data
in patients suggest that periodontal interventions can
improve surrogate serum biomarkers and vascular
responses associated with cardiovascular disease, the
effect of these interventions on true outcomes of
cardiovascular diseases like myocardial infarction
and stroke is presently unknown. Nevertheless,
clinicians and patients should be aware of the con-
sistent association between cardiovascular and peri-
odontal diseases along with the potential preventive
benefits of periodontal interventions.
Cardiovascular disease accounts for 29% of deaths
worldwide and ranks as the second leading cause of
death after infectious and parasitic diseases (100).
Atherosclerosis, which is a major component of car-
diovascular disease, affects one in four persons and
contributes to 39% of deaths annually in the United
States (4). In atherosclerosis, large to medium-sized
muscular and large elastic arteries become occluded
with fibro-lipid lesions called atheromas. End-stage
complications or events associated with atheroscler-
osis include coronary thrombosis, acute myocardial
 2007 The Authors.
Journal compilation  2007 Blackwell Munksgaard
PERIODONTOLOGY 2000
infarction, and stroke. Traditional risk factors related
to behaviors, diet, lifestyle, and family history do
not appear to fully account for the development
of atherosclerosis. Furthermore, despite continued
preventive efforts addressing modifiable risk factors,
mortality rates from cardiovascular disease have re-
mained virtually unchanged over the past decade
in developed countries. Clinicians and investigators
currently appreciate that inflammation appears to
play a pivotal role in the development of athero-
sclerosis. This appreciation has intensified the search
for chronic exposures or infections that potentially
cause inflammation in vessels. Putative infections
that may at least exacerbate atherosclerosis include
cytomegalovirus, herpes simplex virus, Chlamydia
pneumoniae, Helicobacter pylori, and periodontal
disease (71). The major objective of this review is to
provide the reader with a strong fundamental
understanding of the pathogenesis, risk factors, and
current interventions for cardiovascular disease. This
review will also present the latest relevant research
data implicating a relationship between cardiovas-
cular and periodontal diseases.
Inflammation and the
pathogenesis of cardiovascular
disease
Inflammation plays a central and continuous role in
the pathogenesis of atherosclerosis from its initiation
to the development of clinical complications
(Table 1) (58, 60). Normally, endothelial cells, which
form the innermost surface of the artery wall, resist
adhesion by circulating leukocytes. Several exposures
or risk factors for atherosclerosis upset this homeo-
stasis. Factors, such as a smoking, hypertension,
113
Paquette et al.

Table 1. Summary of inflammatory signals and events in atherogenesis. Modified from Ref. (58)
Stages of Endothelial Development of fatty Progression to Plaque rupture
atherogenesis expression of streak complex plaque
adhesion molecules
Cellular and • Endothelial • Diapedesis and • Smooth muscle • Physical disruption
vascular permeability migration of migration from of atherosclerotic
changes • Rolling and monocytes from the media to intima lesion
binding of vessel lumen to • Production and • Thinning and
monocytes to intima accumulation of fibrous fracture of fibrous
endothelial cells • Maturation to tissue in the intima cap
macrophages (fibro-lipid lesion) • Thrombus formation
• Accumulation of • Formation of
cholesterol esters fibrous cap and
and transformation necrotic core
to foam cells
Inflammatory Vascular adhesion Monocyte Platelet-derived growth Matrix metalloproteinases
signals or molecule-1 promoted chemoattractant factor, transforming 1, 8 and 13 promoted
events by oxidized lipids, protein-1 growth factor-b, by interleukin-1,
interleukin-1, tumor and macrophage interleukin-1, CD40 ligand and
necrosis factor-a, colony-stimulating interleukin-6, interfeuron-c
disrupted blood flow, factor tumor necrosis factor-a,
activation of nuclear macrophage colony-
factor-jB pathways stimulating
and reduction in nitric factor, monocyte
oxide chemoattractant protein-1
and CD40

high-saturated-fat diet, obesity hyperglycemia and
insulin resistance, promote endothelial cell expres-
sion of adhesion molecules that allow attachment of
leukocytes to the arterial wall, a seminal event in
inflammation. One such adhesion molecule is vas-
cular cell adhesion molecule-1, which binds mono-
cytes and T lymphocytes, the types of leukocytes
found in early atherosclerotic plaques. Cybulsky
and Gimbrone demonstrated that endothelial cells
expressed vascular cell adhesion molecule-1 in cer-
tain vascular areas prone to lesion formation in rab-
bits fed an atherogenic diet (18). In the same rabbit
model, vascular cell adhesion molecule-1 expression
clearly precedes the appearance of macrophages in
the artery intima (the layer underneath the endo-
thelium) (56). Similarly, mice prone to atherosclerosis
(i.e. because they cannot produce low-density lipo-
protein receptor or apolipoprotein E) but engineered
to express a poorly functioning form of vascular cell
adhesion molecule-1 show a significant reduction in
atherosclerosis as compared to normal vascular cell
adhesion molecule-1-producing controls (19). This
difference in lesion formation occurs despite similar
cholesterol concentrations, lipoprotein profiles and
circulating leukocyte counts in the mice. One recog-
nized molecular initiator of vascular cell adhesion
molecule-1 expression for animals placed on ather-
ogenic diets is the accumulation of modified
lipoprotein particles in the arterial intima. Other
initiators include oxidized lipids (via nuclear factor-
jB-mediated pathways) and pro-inflammatory cyto-
kines such as interleukin-1b and tumor necrosis
factor-a (85).
Atherosclerotic lesions generally develop in specific
areas in animals and humans secondary to the blood
flow characteristics. Laminar blood flow produces
shear stress coinciding with several protective mech-
anisms in vessels such as nitric oxide synthase
expression (33). Enzymatic production of the vasodi-
lator, nitric oxide, can down-regulate vascular cell
adhesion molecule-1 gene expression by inhibiting
nuclear factor-jB activation and platelet aggregation
(22). In contrast, areas of the vasculature prone to
atherogenesis experience disturbed blood flow and a
reduction in these protective mechanisms. For exam-
ple, cultured endothelial cells subjected to disturbed
flow exhibit increased expression of nuclear factor-jB
compared with cells exposed to laminar flow (30).
Development of the fatty streak
The accumulation of monocytes in the vessel intima
is a hallmark event in the development of the early

114
 Cardiovascular disease, inflammation, and periodontal infection
atherosclerotic lesion called the Ôfatty streak.Õ Fol-
lowing adherence to arterial endothelium, monocytes
penetrate the vessel lining via diapedesis or migration
between endothelial cells (Table 1). This cellular
event requires a chemoattractant gradient largely
because of monocyte chemoattractant protein-1.
Mice with inactive low-density lipoprotein receptors
and also lacking the ability to express monocyte
chemoattractant protein-1 have approximately 80%
less lipid deposition and fewer macrophages in the
walls of their aortas despite consuming the same
high-fat diet as compared to monocyte chemoat-
tractant protein-1-producing mice (13). In contrast,
homozygous apolipoprotein-E-deficient mice also
lacking the ability to express the receptor for mono-
cyte chemoattractant protein-1 (CCR2), exhibit sig-
nificantly less atherogenesis than do mice with a
normal CCR2 gene (11). Within the intima, mono-
cytes mature into macrophages, express scavenger
receptors, and engulf modified lipoproteins. Choles-
terol esters accumulate in the cytoplasm of these
macrophages, which transform into Ôfoam cellsÕ
(i.e. lipid-laden macrophages in the vessel intima).
At the same time, the macrophages multiply and
release several growth factors and cytokines, which
amplify and sustain pro-inflammatory signals. One
growth factor, macrophage colony-stimulating factor
appears to be an important mediator of these trans-
formation and proliferation steps. It is also over-ex-
pressed in animal models and human atherosclerotic
plaques (17, 79). Mice prone to atherosclerosis as a
result of reduced expression of the low-density lipo-
protein receptor or the apolipoprotein E gene and
also lacking the ability to express macrophage col-
ony-stimulating factor show slower atherogenesis
and reduced macrophage accumulation as compared
to mice with normal macrophage colony-stimulating
factor expression (75, 90).
T lymphocytes also participate in the pathogenesis
and inflammatory events of atherosclerosis. These
immune cells enter the inflamed artery wall and join
macrophages via a number of interferon-c-inducible
chemokines (e.g., c-IP-10, MIG, and I-TAC) that
interact with the CXCR3 receptor on T lymphocytes
(64). Several other adhesion molecules, chemokines,
cytokines, and growth factors participate in this pro-
cess. For example, the interaction between interleu-
kin-8 and its receptor, CXCR2, can also contribute to
lesion formation in mice (10). Nevertheless, vascular
cell adhesion molecule-1, monocyte chemoattractant
protein-1, and macrophage colony-stimulating factor
appear to be the key inflammatory signals in the
initiation and development of the fatty streak (58).
Progression to complex plaque
While accumulation of foam cells is the hallmark of the
fatty streak, the accumulation of fibrous tissue in ves-
sels typifies the advanced atherosclerotic lesion called
the Ôcomplex plaque.Õ Smooth muscle cells synthesize
the bulk of the extracellular matrix of complex plaques;
hence, their arrival and elaboration of extracellular
matrix provides the transition to a fibrolipid lesion.
Growth factors and cytokines (e.g. platelet-derived
growth factor) liberated from endothelial or infiltrating
monocytes stimulate the migration of smooth muscle
cell from the vessel tunica media into the intima.
Mediators including platelet-derived growth factor,
transforming growth factor-b and interleukin-1 sti-
mulate the smooth muscle cells to produce interstitial
collagen. The formation of complex plaques can occur
at an early age as demonstrated by classic autopsy
studies (99). Indeed, one of six teenagers in the United
States already exhibits pathological intimal thickening
in their coronary arteries (94).
Endothelial cells do not appear to be passive
responders to immunological stimuli from leukocytes
in the formation of complex plaques. For instance,
human endothelial cells exposed to bacterial endo-
toxin express interleukin-1b and interleukin-1a mes-
senger RNA (59). Other cytokines expressed by
vascular wall cells have been identified, including tu-
mor necrosis factor-a, tumor necrosis factor-b, inter-
leukin-6 along with macrophage colony-stimulating
factor and monocyte chemoattractant protein-1 (60).
Another pro-inflammatory cytokine, CD40 ligand
(CD154), can also contribute to this phase of athero-
genesis because interruption of CD40/CD154 signa-
ling slows the initiation and progression of athero-
sclerosis (63). Accordingly, low-density lipoprotein-
receptor-deficient mice fed a high-cholesterol diet and
treated with antibody to CD154 show significantly
smaller atherosclerotic lesions as compared to control
groups (treated with either rat immunoglobulin or
saline only) (82). This provocative finding reported by
Schonbeck et al. illustrates that inflammation influ-
ences the progression of atherosclerosis and that
inhibiting inflammatory events not only prevents the
formation of new lesions but also slows the progres-
sion of existing atherosclerosis.
Plaque rupture
While atheromatous plaques narrow the lumina of
affected vessels and compromise blood flow, the
115
Paquette et al.
major clinical sequelae of atherosclerosis (coronary
thrombosis, myocardial infarction, and stroke) de-
velop following plaque rupture and thrombosis
(Table 1). In coronary arterial thromboses, the
underlying atherosclerotic lesion often does not
produce critical arterial narrowing (36). Coronary
arteries for the most part can enlarge and compen-
sate for developing plaques (i.e. up to 40% stenosis)
thus preserving blood flow to the myocardium (34).
Physical disruption of the atherosclerotic plaque
causes most acute coronary syndromes via thrombus
formation and sudden expansion of the lesion (58). In
the non-ruptured plaque, the Ôfibrous capÕ protects
the blood from the lipid core of the plaque. An intact
fibrous cap owes its biomechanical strength and
stability to interstitial collagen. When the fibrous cap
fractures, blood comes into contact with the lipid
core, and a thrombus forms. Plaques that have rup-
tured and caused fatal thromboses in general have
thin fibrous caps (61).
Inflammation interferes with the integrity of the
fibrous cap in two ways: first, by blocking the creation
of new collagen fibers, and second by stimulating the
destruction of existing collagen. For example, inter-
feron-c produced by T lymphocytes in the plaque
inhibits both basal collagen production and the
stimulatory effects transforming growth factor-b,
platelet-derived growth factor and interleukin-1 (3).
T lymphocytes also promote the destruction of
existing collagen in vulnerable plaques via the pro-
duction of interleukin-1 and CD40 ligand. These
mediators in atherosclerotic plaques stimulate
macrophages to produce collagen-degrading en-
zymes or matrix metalloproteinases 1, 8, and 13 (42,
92). In addition, mast cells in plaques may release the
matrix metalloproteinase-inducer, tumor necrosis
factor-a, as well as serine proteinases, tryptase and
chymase that can activate matrix metalloproteinase
pro-enzymes (53, 80). CD40 ligand from T lympho-
cytes can also promote thrombogenicity of the lipid
core via stimulation of macrophage tissue factor
expression. This potent procoagulant when exposed
to factor VII in the blood, initiates the coagulation
cascade and thrombus formation (62). In summary,
inflammation influences all of the events in athero-
genesis including the final one, plaque rupture.
Risk factors and interventions for
cardiovascular disease
Traditional major risk factors for cardiovascular dis-
ease include cigarette smoking, hypertension (>140/
116
90 mmHg), high low-density lipoprotein cholesterol
(>100 mg/dl), low high-density lipoprotein choles-
terol (<40 mg/dl), diabetes mellitus, family history
of premature coronary heart disease, age (men
>45 years, women >55 years), obesity (body mass
index >30 kg/m2), physical inactivity and an ather-
ogenic diet. It is also recognized that these factors can
interact with each other to increase the risk of car-
diovascular disease in patients (89). For example, the
Framingham Heart Study (n ¼ 32,995) showed that
for various cholesterol levels between 185 and
335 mg/dl, cardiovascular risk was elevated with the
addition of each of the following risk factors: glucose
intolerance, elevated systolic blood pressure, cigar-
ette smoking, and left ventricular hypertrophy on
electrocardiography (50). Data from the Framingham
Heart Study and two other large prospective cohort
studies, the Chicago Heart Association Detection
Project in Industry (n ¼ 35,642) and the Multiple Risk
Factor Intervention Trial (n ¼ 347,978) indicate that
the majority of patients with fatal coronary artery
disease or non-fatal myocardial infarction present
with at least one of four risk factors including cigar-
ette smoking, diabetes mellitus, hyperlipidemia, and
hypertension (35). With fatal coronary artery disease,
exposure to at least one risk factor ranged from 87%
to 100% for all three cohorts. For non-fatal myocar-
dial infarction in the Framingham Heart Study co-
hort, previous exposure to at least one risk factor was
found in 92% of men and 87% of women aged
40–59 years at baseline. Furthermore, another recent
analysis involving 14 international randomized clin-
ical trials (n ¼ 122,458) showed that one of these four
conventional risk factors was present in 84.6% of
men and 80.6% of women with coronary artery dis-
ease (52).
Recent attention has focused on elevated serum
C-reactive protein as a strong and independent risk
factor or predictor of cardiovascular disease events
(68). C-reactive protein is an acute-phase reactant
primarily produced by the liver in response to
infection or trauma. Other tissues may be involved in
its synthesis including smooth muscle cells from
normal coronary arteries and diseased coronary ar-
tery bypass grafts (14, 47). C-reactive protein appears
to be directly involved in augmenting the innate
inflammatory response via induction of prothrom-
botic factors (e.g. plasminogen activator inhibitor-1,
pro-inflammatory adhesion molecules, and mono-
cyte chemoattractant protein-1) and interference
with endothelial nitric oxide synthase (26, 72, 97,
102). In the PhysiciansÕ Health Study, an epidemio-
logical study of over 22,000 healthy middle-aged men
 Cardiovascular disease, inflammation, and periodontal infection
with no clinical evidence of disease, increasing levels
of serum high-sensitivity C-reactive protein at study
entry were associated with up to a threefold increase
in the risk of incident myocardial infarction and a
twofold increase in risk of ischemic stroke (76). When
compared with other potential serum biomarkers
[e.g. homocysteine, lipoprotein(a), interleukin-6,
intracellular adhesion molecule-1, and serum amy-
loid A] and standard lipid measures, C-reactive pro-
tein proved to be the single strongest predictor of
cardiovascular risk in apparently healthy participants
in the Women’s Health Study (n ¼ 28,263) (77, 78).
Accordingly, the relative risk ratio for the highest
versus lowest quartile of serum C-reactive protein
concentrations was 4.4 (95% CI 1.7–11.3). Moreover,
the addition of serum C-reactive protein to tradi-
tional cholesterol screening enhanced cardiovascular
risk prediction and proved to be independent of low-
density lipoprotein cholesterol. Indeed, the poorest
event-free survival in women was among those with
high low-density lipoprotein cholesterol and high
C-reactive protein levels, and the best event-free
survival was among those with low low-density
lipoprotein cholesterol and low C-reactive protein
levels. Individuals with low low-density lipoprotein
cholesterol levels but high C-reactive protein levels
were at higher risk than those with high low-density
lipoprotein cholesterol levels but low C-reactive
protein levels. These data suggest that elevated
C-reactive protein levels may be particularly useful
for identifying asymptomatic individuals who may be
at high risk for future cardiovascular events but who
have average cholesterol levels.
Preventive interventions (primary or secondary) for
cardiovascular disease focus on recognition and
reduction of modifiable risk factors in patients. These
approaches include blood pressure screening, weight
reduction, exercise, smoking cessation, diet modifi-
cation, and patient counseling and education. Initi-
ating and maintaining these lifestyle changes are not
easy tasks for patients. Pharmacological intervention
with the statin class of drugs is used to further reduce
serum lipids and the likelihood of cardiovascular
events, even in those with average low-density lipo-
protein concentrations. Numerous clinical trials have
consistently demonstrated that statins reduce car-
diovascular events by at least 25% (55, 69, 85). In
contrast, the effect of statins and other lipid-lowering
therapies on the extent of vessel stenosis caused
by a plaque is much smaller (13); hence, statins may
have secondary anti-inflammatory effects. Indeed,
C-reactive protein concentrations decrease 15–50%
with statin therapy (2, 70, 93, 96). For patients with
end-stage cardiovascular disease, tertiary preventive
interventions involve physically expanding stenotic
vessels via angioplasty (with or without stenting)
versus revascularization via coronary bypass surgery.
Association between periodontal
and cardiovascular diseases
Patients with periodontal disease share many of the
same risk factors as patients with cardiovascular
disease including age, gender (predominantly male),
lower socioeconomic status, stress, and smoking (7).
Additionally, a large proportion of patients with
periodontal disease also exhibit cardiovascular dis-
ease (95). These observations suggest that periodon-
tal disease and atherosclerosis share similar or
common etiological pathways. In 2003, Scannapieco
et al. conducted a systematic review of the evidence
supporting or refuting any relationship (81). In re-
sponse to the focused question, ÔDoes periodontal
disease influence the initiation/progression of
atherosclerosis and therefore cardiovascular disease,
stroke, and peripheral vascular disease?Õ the investi-
gators identified 31 human studies. Table 2 lists
select influential studies identified in the review plus
additional recent observational studies discussed
below. Although the authors did not perform any
meta-analysis because of the differences in reported
outcomes, the authors noted relative (not absolute)
consistency and concluded, ÔPeriodontal disease may
be modestly associated with atherosclerosis, myo-
cardial infarction, and cardiovascular events.Õ An
accompanying consensus report approved by the
American Academy of Periodontology recommends,
ÔPatients and health care providers should be in-
formed that periodontal intervention may prevent
the onset or progression of atherosclerosis-induced
diseases.Õ
Since this review and consensus report, at least
three meta-analyses on the cardiovascular–perio-
dontal disease association have been conducted and
published. Meurman et al. reported a 20% increase in
cardiovascular disease risk among patients with
periodontal disease (95% CI 1.08–1.32), and an even
higher risk ratio for stroke varying from 2.85 (95% CI
1.78–4.56) to 1.74 (95% CI 1.08–2.81) (67). Similarly,
Vettore and Khader et al. reported relative risk esti-
mates of 1.19 (95% CI 1.08–1.32) and 1.15 (95% CI
1.06–1.25), respectively (51, 98). These meta-analyses
of the available observational human data suggest a
modest but statistically significant increase in the risk
for cardiovascular disease with periodontal disease.
117
118
Table 2. Summary of observational studies (case–control and cohort) investigating an association between periodontal and cardiovascular diseases in human
populations
Paquette et al.

Reference Study design Population Periodontal outcome Cardiovascular outcome Findings and conclusions
or exposure
Matilla et al. (65) Case–control 100 cases and Dental Severity Index (sum of Evidence of myocardial Dental health significantly
102 controls scores for caries, periodontal infarction from ECG and worse in patients with
disease, periapical pathosis, elevated enzyme levels myocardial infarction versus
and pericoronitis) (creatinine phosphokin- controls after adjusting for
ase isoenzyme MB) smoking, social class, smoking,
serum lipids, and diabetes
Matilla et al. (66) Case–control 100 cases Dental Severity Index Clinical diagnosis or Significant association between
radiographically dental infections and severe
confirmed myocardial coronary atheromatosis in men
infarction (but not women)
Arbes et al. (5) Case–control 5,564 subjects Per cent attachment loss of all Self-reported myocardial Positive association between
(NHANES III) teeth (>3 mm) and infarction periodontal disease and
categorized according to four coronary heart disease (OR
levels 3.8 for severe attachment
loss) after adjusting for age,
gender, race, etc.)
DeStefano et al. (24) Cohort 9,760 subjects Subjects classified with no Hospital admission or Periodontitis is associated with
(NHANES I) periodontal disease, with death due to coronary small increased risk for
gingivitis, periodontitis heart disease coronary heart disease
(‡4 mm probing depth) (RR 1.7) among men
or edentulous
Beck et al. (6) Cohort 1,147 men Percent radiographic alveolar Incidence of total and Periodontal disease associated
(Normative bone loss fatal coronary heart with moderate risk for
Aging Study) disease and stroke coronary heart disease
(OR 1.5–1.9) and stroke after
adjusting for age and
cardiovascular disease
risk factors (OR 2.9)
Joshipura et al. (48) Cohort 44,119 subjects Self-reported number of teeth Fatal and non-fatal A small association between
(Health and history of periodontal myocardial infarction or tooth loss and coronary heart
Professionals disease sudden death (revascu disease risk for men (RR 1.7)
Follow-up Study) larization cases excluded)
 Table 2. Continued

Reference Study design Population Periodontal outcome Cardiovascular outcome Findings and conclusions
or exposure
Wu et al. (101) Cohort 9,962 subjects Subjects classified with no Incident cases of stroke Compared to periodontal
(NHANES I periodontal disease, with health, relative risk for stroke
and follow-up) gingivitis, periodontitis with periodontitis was 2.1 and
(‡4 teeth with overt significant
pocketing) or edentulous
Beck et al. (8) Cohort 6,017 subjects Severe periodontitis defined as Carotid artery intima- Periodontitis may influence
(ARIC Study) clinical attachment loss media wall thickness atheroma formation (OR 1.3)
‡3 mm at ‡30% of sites ‡1 mm
Hujoel et al. (44) Cohort 8,032 dentate Periodontal pocketing and Death or hospitalization Periodontitis was not
adults (NHANES I) attachment loss due to coronary heart associated with a significant
disease or revasculariza- increased risk for coronary
tion obtained from heart disease
medical records
Howell et al. (43) Cohort 22,037 male subjects Self-reported presence or Incident fatal and non- No significant association
(Physician’s Health absence of periodontal fatal myocardial between self-reported
Study I) disease at baseline infarction or stroke periodontal disease and
cardiovascular disease events
Hung et al. (45) Cohort 41,407 men from the Self-reported tooth loss at Incident fatal and non- For men with tooth loss, the
HPFS and 58,974 baseline fatal myocardial relative risk for coronary
women from the infarction or stroke heart disease was 1.36. For
NHS women with tooth loss, the
relative risk was 1.64
Pussinen et al. (73) Cohort 6,950 Finnish subjects Serum antibodies to Incident fatal or non-fatal Seropositive subjects had an
in the Mobile Clinic P. gingivalis or stroke OR of 2.6 for stroke
Health Survey A. actinomycetemcomitans
Beck et al. (9) Cohort 15,792 subjects (ARIC Serum antibodies to Carotid artery Presence of antibody to
Study) periodontal pathogens intima-media wall C. rectus was associated with
thickness ‡1 mm carotid atherosclerosis
(OR 2.3)
Engebretson et al. (29) Cohort 203 subjects from Radiographic alveolar bone Carotid plaque thickness Severe periodontal bone loss
INVEST loss via ultrasonography was independently associated
with carotid atherosclerosis
(OR 3.64)
Cardiovascular disease, inflammation, and periodontal infection

119
Paquette et al.

Recent findings from several worldwide population

(RR 1.29) and stroke (RR 1.12)

Tooth loss was associated with
was independently associated

an increased odds for death

studies warrant detailed consideration. These studies

Severe periodontal bone loss

with carotid atherosclerosis

from myocardial infarction

Findings and conclusions
include the Atherosclerosis Risk in Communities
Study, the Health Professional Follow-up Study, the
Nurses Health Study, and the Oral Infections and
Vascular Disease Epidemiology Study conducted in
the United States. Other studies have involved pop-

(OR 3.64)
ulations from Sweden, Finland, and China.
Beck et al. have collected periodontal probing data
on 6,017 persons, 52–75 years of age, participating in
the Atherosclerosis Risk in Communities study (8, 9,
27). These investigators assessed both the presence of
Cardiovascular outcome

myocardial infarction
clinical coronary heart disease (myocardial infarction
or revascularization procedure) and subclinical
intima-media wall
thickness ‡1 mm

Incidence of fatal

atherosclerosis (carotid artery intima-media wall

thickness using B-mode ultrasound) as dependent
Carotid artery

variables in the population. Individuals with both

or stroke

high attachment loss (‡10% of sites with attachment

loss >3 mm) and high tooth loss exhibited elevated
odds of prevalent coronary heart disease as com-
pared to individuals with low attachment loss and
low tooth loss (odds ratio 1.5, 95% CI 1.1–2.0 and
Subgingival bacterial burden

odds ratio 1.8, CI 1.4–2.4, respectively) (27). A second

logistic regression analysis indicated a significant
Periodontal outcome

association between severe periodontitis and thick-

ened carotid arties after adjusting for covariates like
age, gender, diabetes, lipids, hypertension, and
or exposure

Tooth loss

smoking (8). Accordingly, the odds ratio for severe

periodontitis (i.e. 30% or more of sites with ‡3 mm
clinical attachment loss) and subclinical carotid
atherosclerosis was 1.31 (95% CI 1.03–1.66). In a
third report, these investigators quantified serum
immunoglobulin G antibody levels specific for 17
29,584 rural Chinese
1,056 subjects from

periodontal organisms using a whole bacterial

ECG, electrocardiogram; OR, odds ratio; RR, relative risk. Modified from Ref. (81).

checkerboard immunoblotting technique (9). Ana-

Population

lyzing the mean carotid intima-media wall thickness

subjects
INVEST

(‡1 mm) as the outcome and serum antibody levels

as exposures for this same population, the investi-
gators noted that the presence of antibody to Cam-
pylobacter rectus increased the risk for subclinical
atherosclerosis twofold (odds ratio 2.3, 95% CI 1.83–
Study design

2.84). In particular, individuals with both high C.

rectus and Peptostreptococcus micros antibody titers
Cohort

Cohort

had almost twice the prevalence of carotid athero-

sclerosis as compared to those with only a high C.
rectus antibody (8.3% versus 16.3%). Stratification by
Desvarieux et al. (25)
Table 2. Continued

smoking indicated that all microbial models signifi-

cant for smokers were also significant for never
Abnet et al. (1)

smokers except for Porphyromonas gingivalis. Thus,

Reference

clinical signs of periodontitis are associated with

coronary heart disease and subclinical atheroscler-
osis in the Atherosclerosis Risk in Communities
population, and exposures to specific periodontal

120
 Cardiovascular disease, inflammation, and periodontal infection
pathogens significantly increase the risk for athero-
sclerosis in smoking and non-smoking subjects.
Hung et al. assessed self-reported periodontal dis-
ease outcomes and incident cardiovascular disease in
two extant databases, the Health Professional Follow-
up Study (n ¼ 41,407 men followed for 12 years) and
the Nurses Health Study (n ¼ 58,974 women fol-
lowed for 6 years) (45). After controlling for import-
ant cardiovascular risk factors, men with a low
number of reported teeth (£10 at baseline) had a
significantly higher risk of coronary heart disease
(relative risk 1.36 95% CI 1.11–1.67) as compared to
men with a high number of teeth (25 or more). For
women with the same reported extent of tooth loss,
the relative risk for coronary heart disease was 1.64
(95% CI 1.31–2.05) as compared to women with at
least 25 teeth. The relative risks for fatal coronary
heart disease events increased to 1.79 (95% CI 1.34–
2.40) for men and 1.65 (95% CI 1.11–2.46) for women
with tooth loss respectively. In a second report, the
investigators evaluated the association between self-
reported periodontal disease and serum elevations in
cardiovascular disease biomarkers cross-sectionally
in a subset of Health Professional Follow-up Study
participants (n ¼ 468 men) (49). Serum biomarkers
included C-reactive protein, fibrinogen, factor VII,
tissue plasminogen activator, low-density lipoprotein
cholesterol, von Willebrand factor, and soluble tumor
necrosis factor receptors 1 and 2. In multivariate
regression models controlling for age, cigarette
smoking, alcohol intake, physical activity, and aspirin
intake, self-reported periodontal disease was associ-
ated with significantly higher levels of C-reactive
protein (30% higher among periodontal cases com-
pared with non-cases), tissue plasminogen activator
(11% higher), and low-density lipoprotein cholesterol
(11% higher). These analyses reveal significant
associations between self-reported number of teeth
at baseline and risk of coronary heart disease
and between self-reported periodontal disease and
serum biomarkers of endothelial dysfunction and
dyslipidemia.
One population study, the Oral Infections and
Vascular Disease Epidemiology Study (or INVEST),
has been planned a priori and conducted exclusively
to evaluate the association between cardiovascular
disease and periodontal outcomes in a cohort pop-
ulation. Engebretson et al. reported that for a group
of 203 stroke-free subjects (ages 54–94 years) at
baseline, mean carotid plaque thickness (measured
with B-mode ultrasound) was significantly greater
among dentate subjects with severe periodontal bone
loss (‡50% measured radiographically) as compared
to those with less bone loss (<50%) (29). Indeed, the
group noted a clear dose–response relationship when
they plotted subject tertiles of periodontal bone loss
against carotid plaque thickness graphically. The
investigators next collected subgingival plaque from
1,056 subjects and tested for the presence of 11
known periodontal bacteria using DNA techniques
(25). The investigators found that cumulative perio-
dontal bacterial burden was significantly related to
carotid intima-media wall thickness after adjusting
for cardiovascular disease risk factors. Whereas mean
intima-media wall thickness values were similar
across burden tertiles for putative (orange complex)
and health-associated bacteria, values rose with each
tertile of etiological bacterial burden (Actinobacillus
ancinomycetemcomitans, P. gingivalis, Treponema
denticola and Tannerella forsythia). Similarly, white
blood cell values (but not serum C-reactive protein)
increased across these burden tertiles. These data
from INVEST provide evidence of a direct relation-
ship between periodontal microbiology and sub-
clinical atherosclerosis independent of C-reactive
protein.
Consistent associations between periodontal out-
comes and atherosclerosis have been recently dem-
onstrated among populations in Europe and Asia. For
131 adult Swedes, mean carotid intima-media wall
thickness values were significantly higher in subjects
with clinical and/or radiographic evidence of perio-
dontal disease as compared to periodontally healthy
controls (91). Multiple logistic regression analysis
identified periodontal disease as a principal inde-
pendent predictor of carotid atherosclerosis with an
odds ratio of 4.64 (95% CI 1.64–13.10). Pussinen et al.
monitored antibody responses for A. actinomyce-
temcomitans and P. gingivalis among 6,950 Finnish
subjects for whom cardiovascular disease outcomes
over 13 years were available (Mobile Clinic Health
Survey) (73). Compared with the subjects who were
seronegative for these pathogens, seropositive sub-
jects had an odds ratio of 2.6 (95% CI 1.0–7.0) for a
secondary stroke. In a second report on 1,023 men
(Kuopio Ischemic Heart Disease Study), Pussinen
et al. observed that cases with myocardial infarction
or coronary heart disease death were more often
seropositive for A. actinomycetemcomitans than those
controls who remained healthy (15.5% versus 10.2%)
(74). In the highest tertile of A. actinomycetemcomi-
tans antibodies, the relative risk for myocardial
infarction or coronary heart disease death was 2.0
(95% CI 1.2–3.3) compared with the lowest tertile.
For P. gingivalis antibody responses, the relative risk
was 2.1 (95% CI 1.3–3.4). Abnet et al. recently
121
Paquette et al.
published findings from a cohort study of 29,584
healthy, rural Chinese adults monitored for up to
15 years (1). Tooth loss was evaluated as an exposure
outcome for periodontal disease, and mortality from
heart disease or stroke were modeled as dependent
variables. Individuals with greater than the age-
specific median number of teeth lost exhibited a sig-
nificantly increased risk of death from myocardial
infarction (relative risk 1.28, 95% CI 1.17–1.40) and
stroke (relative risk 1.12, 95% CI 1.02–1.23). These
elevated risks were present in both men and women
irrespective of smoking status. Collectively, these
findings indicate consistent associations for perio-
dontal disease and pathogenic exposures with cardio-
vascular disease for European and Asian populations.
Biological plausibility and
experimental evidence
Since periodontal infections result in low-grade
bacteremias and endotoxemias in affected patients
(83, 86), systemic effects on vascular physiology via
these exposures appear biologically plausible. Four
specific pathways have been proposed to explain the
plausibility of a link between cardiovascular disease
and periodontal infection. These pathways (acting
independently or collectively) include:
• direct bacterial effects on platelets,
• autoimmune responses,
• invasion and/or uptake of bacteria in endothelial
cells and macrophages,
• endocrine-like effects of pro-inflammatory media-
tors.
In support of the first pathway, two oral bacteria,
P. gingivalis and Streptococcus sanguis, express viru-
lence factors, the collagen-like platelet aggregation
associated proteins, that induce platelet aggregation
in vitro and in vivo (39, 40). Second, autoimmune
mechanisms may play a role because antibodies that
cross-react with periodontal bacteria and human
heat-shock proteins have been identified (41, 87).
Deshpande et al. have thirdly demonstrated that the
P. gingivalis can invade aortic and heart endothelial
cells via fimbriae (23). Several investigative groups
have independently identified specific oral pathogens
in atheromatous tissues (16, 37). In addition, macro-
phages incubated in vitro with P. gingivalis and
low-density lipoprotein take up the bacteria intra-
celluarly and transform into foam cells (31). In the
last potential pathway, systemic pro-inflammatory
mediators are upregulated for endocrine-like effects
in vascular tissues, and studies consistently demon-
122
strate elevations in C-reactive protein and fibrinogen
among periodontally diseased subjects (88, 101).
Experiments with animal models demonstrate
that specific infections with periodontal pathogens
accelerate atherogenesis. For example, inbred het-
erozygous and homozygous apolipoprotein-E-defici-
ent mice exhibit increased aortic atherosclerosis
when challenged orally or intravenously with invasive
strains of P. gingivalis (15, 32, 54, 57). While P. gin-
givalis challenges increased aortic atherosclerosis in
apolipoprotein-E-deficient mice in a hypercholes-
terolemic background only, normocholesterolemic
pigs were recently shown to develop both coronary
and aortic lesions with P. gingivalis challenges (12).
This finding suggests that P. gingivalis bacteremias
may exert an atherogenic stimulus independent of
the high cholesterol levels in pigs. It is worth noting
that a wide range of P. gingivalis doses was used in
these animal studies. While the clinically relevant
dose for human subjects is unknown at present, it
probably varies greatly (21, 38, 46). Importantly,
P. gingivalis challenge enhances atherosclerosis, de-
spite different routes of administration and dosing
regimens, in both species. The P. gingivalis 16 ribo-
somal DNA was detected by polymerase chain reac-
tion in atheromas from some but not all of these
mutant mice and pigs. These experiments suggest
that both the host response and the virulence of the
specific P. gingivalis strains appear to be important
variables in these infection–atherogenesis models.
Evidence in humans demonstrating the beneficial
effects of periodontal therapy on cardiovascular dis-
ease outcomes is limited and indirect at present.
D’Auito et al. recently demonstrated that periodon-
titis patients treated with scaling and root planing
exhibited significant serum reductions in the car-
diovascular disease biomarkers, C-reactive protein
and interleukin-6 (20). In particular, patients who
clinically responded to periodontal therapy in terms
of pocket depth reductions were four times more
likely to exhibit serum decreases in C-reactive protein
relative to patients with a poor clinical periodontal
response. Elter et al. also report decreases in these
serum biomarkers plus improved endothelial func-
tion (i.e. flow-mediated dilation of the brachial
artery) for 22 periodontitis patients treated with
Ôcomplete mouth disinfectionÕ (i.e. scaling and root
planing, periodontal flap surgery and extraction of
hopeless teeth within a 2-week period) (28). Similarly,
Seinost et al. tested endothelial function in 30 pa-
tients with severe periodontitis and compared this
with 31 periodontally healthy control subjects (84).
Before the interventions, flow-mediated dilation was
 Cardiovascular disease, inflammation, and periodontal infection
significantly lower in patients with periodontitis than
in control subjects. Periodontitis patients with favo-
rable clinical responses to non-surgical periodontal
therapy (i.e. scaling and root planing, topical and
peroral antimicrobials plus mechanical retreatment)
exhibited concomitant improvements in flow-medi-
ated dilatation of the brachial artery and serum
C-reactive protein concentrations. While the effects
of periodontal therapy on cardiovascular disease
events in patients have yet to be determined, the
available pilot data suggest that periodontal therapies
can improve surrogate cardiovascular disease out-
comes like serum biomarkers and endothelial dys-
function.
Conclusions
Inflammation plays a central role in atherogenesis
from endothelial cell expression of adhesion mole-
cules to the development of the fatty streak, estab-
lished plaque, and finally plaque rupture. Human
observational studies and experimental animal mod-
els continue to implicate periodontal infection as a
systemic exposure that may perpetuate these inflam-
matory events in vessels. Although treatments aimed
at decreasing periodontal infection and inflammation
can reduce serum inflammatory biomarkers predic-
tive of cardiovascular disease and improve vascular
responses, the clinical relevance of these surrogate
changes to reduced risks for myocardial infarction or
stroke are not known at this time. Nevertheless,
clinicians and patients should be knowledgeable
about this consistent association and the potential
preventive benefits of periodontal interventions.
References
1. Abnet CC, Qiao YL, Dawsey SM, Dong ZW, Taylor PR,
Mark SD. Tooth loss is associated with increased risk of
total death and death from upper gastrointestinal cancer,
heart disease, and stroke in a Chinese population-based
cohort. Int J Epidemiol 2005: 34: 467–474.
2. Albert MA, Danielson E, Rifai N, Ridker PM. Effect of
statin therapy on C-reactive protein levels: the pravastatin
inflammation/CRP evaluation (PRINCE): a randomized
trial and cohort study. J Am Med Assoc 2001: 286: 64–70.
3. Amento EP, Ehsani N, Palmer H, Libby P. Cytokines and
growth factors positively and negatively regulate intersti-
tial collagen gene expression in human vascular smooth
muscle cells. Arterioscler Thromb 1991: 11: 1223–1230.
4. American Heart Association. Heart, disease and stroke
statistics – 2004 update. Dallas, TX: American Heart
Association, 2003.
5. Arbes SJ. Slade GD. and Beck JD. 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.
6. Beck JD, Garcia R, Heiss G, Vokonas P, Offenbacher S.
Periodontal disease and cardiovascular disease. J Period-
ontol 1996: 67: 1123–1137.
7. Beck JD, Offenbacher S, Williams RC, Gibbs P, Garcia K.
Periodontitis: a risk factor for coronary heart disease?
Ann Periodontol 1998: 3: 127–141.
8. Beck J, Elter J, Heiss G, Couper D, Mauriello S, Offenba-
cher S. Relationship of periodontal disease to carotid ar-
tery intima-media wall thickness: the Atherosclerosis Risk
in Communities (ARIC) Study. Arterioscler Thromb Vasc
Biol 2001: 21: 1816–1822.
9. Beck JD, Eke P, Lin D, Madianos P, Couper D, Moss K,
Elter J, Heiss G, Offenbacher S. Associations between IgG
antibody to oral organisms and carotid intima-medial
thickness in community-dwelling adults. Atherosclerosis
2005: 183: 342–348.
10. Boisvert WA, Santiago R, Curtiss LK, Terkeltaub RA.
A leukocyte homologue of the IL-8 receptor CXCR-2
mediates the accumulation of macrophages in athero-
sclerotic lesions of LDL receptor-deficient mice. J Clin
Invest 1998: 101: 353–363.
11. Boring L, Gosling J, Cleary M, Charo IF. Decreased lesion
formation in CCR2)/) mice reveals a role for chemokines in
the initiation of atherosclerosis. Nature 1998: 394: 894–897.
12. Brodala NME, Bellinger DA, Damrongsri D, Offenbacher
S, Beck J, Madianos P, Sotres D, Chang YL, Koch G,
Nichols TC. Porphyromonas gingivalis bacteremia indu-
ces coronary and aortic atherosclerosis in normocholes-
terolemic and hypercholesterolemic pigs. Arterioscler
Thromb Vasc Biol 2005: 25: 1446–1451.
13. Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC,
Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic P,
Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant
vitamins, or the combination for the prevention of cor-
onary disease. N Engl J Med 2001: 345: 1583–1592.
14. Calabro P, Willerson JT, Yeh ET. Inflammatory cytokines
stimulated C-reactive protein production by human cor-
onary artery smooth muscle cells. Circulation 2003: 108:
1930–1932.
15. Chi H, Messas E, Levine RA, Graves DT, Amar S. Inter-
leukin-1 receptor signaling mediates atherosclerosis
associated with bacterial exposure and/or a high-fat diet
in a murine apolipoprotein E heterozygote model: phar-
macotherapeutic implications. Circulation 2004: 110:
1678–1685.
16. Chiu B. Multiple infections in carotid atherosclerotic
plaques. Am Heart J 1999: 138: 534–536.
17. Clinton SK, Underwood R, Hayes L, Sherman ML, Kufe
DW, Libby P. Macrophage colony-stimulating factor gene
expression in vascular cells and in experimental and hu-
man atherosclerosis. Am J Pathol 1992: 140: 301–316.
18. Cybulsky MI, Gimbrone MA Jr. Endothelial expression of a
mononuclear leukocyte adhesion molecule during ather-
ogenesis. Science 1991: 251: 788–791.
19. Cybulsky MI, Iiyama K, Li H, Zhu S, Chen M, Iiyama M,
Davis V, Gutierrez-Ramos JC, Connelly PW, Milstone S. A
major role for VCAM-1, but not ICAM-1, in early athero-
sclerosis. J Clin Invest 2001: 107: 1255–1262.
123
Paquette et al.
20. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease
and C-reactive protein-associated cardiovascular risk.
J Periodontal Res 2004: 39: 236–241.
21. Daly CG, Mitchell DH, Highfield JE, Grossberg DE, Stew-
art D. Bacteremia due to periodontal probing: a clinical
and microbiological investigation. J Periodontol 2001: 72:
210–214.
22. De Caterina R, Libby P, Peng HB, Thannickal VJ, Raja-
vashisth TB, Gimbrone MA Jr, Shin WS, Liao JK. Nitric
oxide decreases cytokine-induced endothelial activation.
Nitric oxide selectively reduces endothelial expression of
adhesion molecules and proinflammatory cytokines.
J Clin Invest 1995: 96: 60–68.
23. Deshpande RG, Khan MB, Genco CA. Invasion of aortic
and heart endothelial cells by Porphyromonas gingivalis.
Infect Immun 1998: 66: 5337–5343.
24. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell
CM. Dental disease and risk of coronary heart disease and
mortality. Br Med J 1993: 306: 688–691.
25. Desvarieux M, Demmer RT, Rundek T, Boden-Albala B,
Jacobs DR Jr, Sacco RL, Papapanou PN. Periodontal
microbiota and carotid intima-media thickness: the Oral
Infections and Vascular Disease Epidemiology Study
(INVEST). Circulation 2005: 111: 576–582.
26. Devaraj S, Xu DY, Jialal I. C-reactive protein increases
plasminogen activator inhibitor-1 expression and activity
in human aortic endothelial cells implications for the
metabolic syndrome and atherothrombosis. Circulation
2003: 107: 398–404.
27. Elter JR, Champagne CM, Offenbacher S, Beck JD. Rela-
tionship of periodontal disease and tooth loss to prevalence
of coronary heart disease. J Periodontol 2004: 75: 782–790.
28. Elter JR, Hinderliter AL, Offenbacher S, Beck JD, Caughey
M, Brodala N, Madianos PN. The effects of periodontal
therapy on vascular endothelial function: a pilot trial.
Am Heart J 2006: 151: 47.e1–47.e6.
29. Engebretson SP, Lamster IB, Elkind MS, Rundek T, Serman
NJ, Demmer RT, Sacco RL, Papapanou PN, Desvarieux M.
Radiographic measures of chronic periodontitis and
carotid artery plaque. Stroke 2005: 36: 561–566.
30. Gerszten RE, Garcia-Zepeda EA, Lim YC, Yoshida M, Ding
HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rose-
nzweig A. MCP-1 and IL-8 trigger firm adhesion of
monocytes to vascular endothelium under flow condi-
tions. Nature 1999: 398: 718–723.
31. Giacona MB, Pappanou PN, Lamster IB, Rong LL, D’Agati
VD, Schmidt AM, Lalla E. Porphyromonas gingivalis
induces uptake by human macrophages and promotes
foam cell formation in vitro. FEMS Microbiol Lett 2004:
241: 95–101.
32. Gibson FC III, Hong C, Chou HH, Yumoto H, Chen J, Lien E,
Wong J, Genco CA. Innate immune recognition of invasive
bacteria accelerates atherosclerosis in apolipoprotein
E-deficient mice. Circulation 2004: 109: 2801–2806.
33. Gimbrone MA Jr, Topper JN, Nagel T, Anderson KR,
Garcia-Cardena G. Endothelial dysfunction, hemody-
namic forces, and atherogenesis. Ann N Y Acad Sci 2000:
902: 230–239.
34. Glagov S, Weisenberg E, Zarins CK, Stankunavicius R,
Kolettis GJ. Compensatory enlargement of human
atherosclerotic coronary arteries. N Engl J Med 1987: 316:
1371–1375.
124
35. Greenland P, Knoll MD, Stamler J, Neaton JD, Dyer AR,
Garside DB, Wilson PW. Major risk factors as antecedents
of fatal and nonfatal coronary heart disease events. J Am
Med Assoc 2003: 290: 891–897.
36. Hackett D, Davies G, Maseri A. Pre-existing coronary
stenoses in patients with first myocardial infarction are
not necessarily severe. Eur Heart J 1988: 9: 1317–1323.
37. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ.
Identification of periodontal pathogens in atheromatous
plaques. J Periodontol 2000: 71: 1554–1560.
38. Haynes WG, Stanford C. Periodontal disease and athero-
sclerosis: from dental to arterial plaque. Arterioscler
Thromb Vasc Biol 2003: 23: 1309–1311.
39. Herzberg ME, Meyer MW. Dental plaque, platelets and
cardiovascular diseases. Ann Periodontol 1998: 3: 152–160.
40. Herzberg MC, Myer MW. Effects of oral flora on platelets:
possible consequences in cardiovascular disease. J Perio-
dontol 1996: 67: 1138–1142.
41. Hinode D, Nakamura R, Grenier D, Mayrand D. Cross-
reactivity of specific antibodies directed to heat shock
proteins from periodontopathogenic bacteria and of hu-
man origin. Oral Microbiol Immunol 1998: 13: 55–58.
42. Horton DB, Libby P, Schonbeck U. Ligation of CD40 on
vascular smooth muscle cells mediates loss of interstitial
collagen via matrix metalloproteinase activity. Ann N Y
Acad Sci 2001: 947: 329–336.
43. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Chris-
ten WG. Periodontal disease and risk of subsequent car-
diovascular disease in U.S. male physicians. J Am Coll
Cardiol 2001: 37: 445–450.
44. Hujoel PP, Drangsholt M, Spiekerman C, Depouen TA.
Periodontal disease and coronary heart disease risk. JAMA
2000: 284: 1406–1410.
45. Hung HC, Joshipura KJ, Colditz G, Manson JE, Rimm EB,
Speizer FE, Willet WC. The association between tooth loss
and coronary heart disease in men and women. J Public
Health Dent 2004: 64: 209–215.
46. Ide M, Jagdev D, Coward PY, Crook M, Barclay GR, Wilson
RF. The short-term effects of treatment of chronic perio-
dontitis on circulating levels of endotoxin, C-reactive
protein, tumor necrosis factor-alpha, and interleukin-6.
J Periodontol 2004: 75: 420–428.
47. Jabs WJ, Theissing E, Nitschke M, Bechtel JF, Duchrow M,
Mohamed S, Jahrbeck B, Sievers HH, Steinhoff J, Bartels
C. Local generation of C-reactive protein in diseased
coronary artery venous bypass grafts and normal vascular
tissue. Circulation 2003: 108: 1428–1431.
48. Joshipura KJ, Rimm EB, Douglas CW, Trichopoulos D,
Ascherio A, Willett WC. Poor oral health and coronary
heart disease. J Dent Res 1996: 75: 1631–1636.
49. Joshipura KJ, Wand HC, Merchant AT, Rimm EB. Perio-
dontal disease and biomarkers related to cardiovascular
disease. J Dent Res 2004: 83: 151–155.
50. Kannel WB. High-density lipoproteins epidemiologic
profile and risks of coronary artery disease. Am J Cardiol
1983: 52(Suppl.): 9B–12B.
51. Khader YS, Albashaireh ZS, Alomari MA. Periodontal dis-
eases and the risk of coronary heart and cerebrovascular
diseases: a meta-analysis. J Periodontol 2004: 75: 1046–
1053.
52. Khot UN, Khot MB, Bajzer CT, Sapp SK, Ohman EM,
Brener SJ, Ellis SE, Lincoff AM, Topol EJ. Prevalence of
 Cardiovascular disease, inflammation, and periodontal infection
conventional risk factors in patients with coronary heart
disease. J Am Med Assoc 2003: 290: 898–904.
53. Kovanen PT, Kaartinen M, Paavonen T. Infiltrates of
activated mast cells at the site of coronary atheromatous
erosion or rupture in myocardial infarction. Circulation
1995: 92: 1084–1088.
54. Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP,
Tucker S, Lu Y, Papapanou PN, Schmidt AM. Oral infec-
tion with a periodontal pathogen accelerates early
atherosclerosis in apolipoprotein E-null mice. Arterioscler
Thromb Vasc Biol 2003: 23: 1405–1411.
55. LaRosa JC, He J, Vupputuri S. Effect of statins on risk of
coronary disease: a meta-analysis of randomized con-
trolled trials. J Am Med Assoc 1999: 282: 2340–2346.
56. Li H, Cybulsky MI, Gimbrone MA Jr, Libby P. An athero-
genic diet rapidly induces VCAM-1, a cytokine-regulatable
mononuclear leukocyte adhesion molecule, in rabbit aor-
tic endothelium. Arterioscler Thromb 1993: 13: 197–204.
57. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphy-
romonas gingivalis infection accelerates the progression
of atherosclerosis in a heterozygous apolipoprotein
E-deficient murine model. Circulation 2002: 105: 861–867.
58. Libby P. Inflammation and cardiovascular disease
mechanisms. Am J Clin Nutr 2006: 83(Suppl.):456S–460S.
59. Libby P, Ordovas JM, Auger KR, Robbins AH, Birinyi LK,
Dinarello CA. Endotoxin and tumor necrosis factor induce
interleukin-1 gene expression in adult human vascular
endothelial cells. Am J Pathol 1986: 124: 179–185.
60. Libby P, Ridker PM, Maseri A. Inflammation and athero-
sclerosis. Circulation 2002: 105: 1135–1143.
61. Loree HM, Kamm RD, Stringfellow RG, Lee RT. Effects of
fibrous cap thickness on peak circumferential stress in
model atherosclerotic vessels. Circ Res 1992: 71: 850–858.
62. Mach F, Schonbeck U, Bonnefoy JY, Pober JS, Libby P.
Activation of monocyte/macrophage functions related to
acute atheroma complication by ligation of CD40:
induction of collagenase, stromelysin, and tissue factor.
Circulation 1997: 96: 396–399.
63. Mach F, Schonbeck U, Sukhova GK, Atkinson E, Libby P.
Reduction of atherosclerosis in mice by inhibition of
CD40 signalling. Nature 1998: 394: 200–203.
64. Mach F, Sauty A, Iarossi AS, Sukhova GK, Neote K, Libby
P, Luster AD. Differential expression of three T lympho-
cyte-activating CXC chemokines by human atheroma-
associated cells. J Clin Invest 1999: 104: 1041–1050.
65. Matilla K, Nieminen M, Valtonen V, Rasi V, Kesaniemi Y,
Syrjala S, Jungul P, Isoluoma M, Hietaniemi K, Jokinen M,
Huttunen J. Association between dental health and acute
myocardial infarction. Br Med J 1989: 298: 779–782.
66. Matilla KJ, Valle MS, Nieminen MS, Valtonen VV, Hie-
taniemi KL. Dental infections and coronary atheroscler-
osis. Atherosclerosis 1993: 103: 205–211.
67. Meurman JH, Sanz M, Janket SJ. Oral health, athero-
sclerosis and cardiovascular disease. Crit Rev Oral Biol
Med 2004: 15: 403–413.
68. Mora S, Ridker PM. Justification for the use of Statins in
Primary Prevention: an Intervention Trial Evaluating
Rosuvastatin (JUPITER) – can C-reactive protein be used
to target statin therapy in primary prevention? Am J
Cardiol 2006: 97(Suppl.): 33A–41A.
69. MRC/BHF Heart Protection Study of cholesterol lowering
with simvastatin in 20,536 high-risk individuals: a
randomised placebo-controlled trial. Lancet 2002: 360:
7–22.
70. Nissen SE, Tuzcu EM, Schoenhagen P, Brown BG, Ganz P,
Vogel RA, Crowe T, Howard G, Cooper CJ, Brodie B,
Grines CL, DeMaria AN: REVERSAL Investigators. Effect of
intensive compared with moderate lipid-lowering therapy
on progression of coronary atherosclerosis: a randomized
controlled trial. J Am Med Assoc 2004: 291: 1071–1080.
71. O’Connor S, Taylor C, Campbell LA, Epstein S, Libby P.
Potential infectious etiologies of atherosclerosis: a multi-
factorial perspective. Emerg Infect Dis 2001: 7: 780–787.
72. Pasceri V, Willerson JT, Yeh ET. Direct proinflammatory
effect of C-reactive protein on human endothelial cells.
Circulation 2000: 102: 2165–2168.
73. Pussinen PJ, Alfthan G, Rissanen H, Reunanen A, Asikai-
nen S, Knekt P. Antibodies to periodontal pathogens and
stroke risk. Stroke 2004: 35: 2020–2023.
74. Pussinen PJ, Nyyssonen K, Alfthan G, Salonen R, Lauk-
kanen JA, Salonen JT. Serum antibody levels to Actino-
bacillus actinomycetemcomitans predict the risk for
coronary heart disease. Arterioscler Thromb Vasc Biol
2005: 25: 833–838.
75. Rajavashisth T, Qiao JH, Tripathi S, Tripathi J, Mishra N,
Hua M, Wang XP, Loussararian A, Clinton S, Libby P, Lusis
A. Heterozygous osteopetrotic (op) mutation reduces
atherosclerosis in LDL receptor-deficient mice. J Clin
Invest 1998: 101: 2702–2710.
76. Ridker PM, Cushman M, Stampfer MJ, Tracy RP, Henne-
kens CH. Inflammation, aspirin, and the risk of cardio-
vascular disease in apparently healthy men. N Engl J Med
1997: 336: 973–979.
77. Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive
protein and other markers of inflammation in the pre-
diction of cardiovascular disease in women. N Engl J Med
2000: 342: 836–843.
78. Ridker PM, Rifai N, Rose L, Buring JE, Cook NR. Com-
parison of C-reactive protein and low-density lipoprotein
cholesterol levels in the prediction of first cardiovascular
events. N Engl J Med 2002: 347: 1557–1565.
79. Rosenfeld ME, Yla-Herttuala S, Lipton BA, Ord VA,
Witztum JL, Steinberg D. Macrophage colony-stimula-
ting factor mRNA and protein in atherosclerotic lesions
of rabbits and humans. Am J Pathol 1992: 140: 291–
300.
80. Saren P, Welgus HG, Kovanen PT. TNF-alpha and IL-1beta
selectively induce expression of 92-kDa gelatinase by
human macrophages. J Immunol 1996: 157: 4159–4165.
81. Scannapieco FA, Bush RB, Paju S. Associations between
periodontal disease and risk for atherosclerosis, cardio-
vascular disease, and stroke. A systematic review. Ann
Periodontol 2003: 8: 38–53.
82. Schonbeck U, Sukhova GK, Shimizu K, Mach F, Libby P.
Inhibition of CD40 signaling limits evolution of estab-
lished atherosclerosis in mice. Proc Natl Acad Sci U S A
2000: 97: 7458–7463.
83. Sconyers JR, Crawford JJ, Moriarty JD. Relationship of
bacteremia to toothbrushing in patients with periodonti-
tis. J Am Dent Assoc 1973: 87: 616–622.
84. Seinost G, Wimmer G, Skerget M, Thaller E, Brodmann M,
Gasser R, Bratschko RO, Pilger E. Periodontal treatment
improves endothelial dysfunction in patients with severe
periodontitis. Am Heart J 2005: 149: 1050–1054.
125
Paquette et al.
85. Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G,
Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McIn-
nes GT, Mehlsen J, Nieminen M, O’Brien E, Ostergren J;
ASCOT Investigators. Prevention of coronary and stroke
events with atorvastatin in hypertensive patients who
have average or lower-than-average cholesterol concen-
trations, in the Anglo-Scandinavian Cardiac Outcomes
Trial–Lipid Lowering Arm (ASCOT-LLA): a multicentre
randomised controlled trial. Lancet 2003: 361: 1149–1158.
86. Silver JG, Martin AW, McBride BC. Experiment transient
bacteremias in human subjects with varying degrees of
plaque accumulation and gingival inflammation. J Clin
Periodontol 1980: 4: 92–99.
87. Sims TJ, Lernmark A, Mancl LA, Schifferle RE, Page RC,
Persson GR. Serum IgG to heat shock proteins and Por-
phyromonas gingivalis antigens in diabetic patients with
periodontitis. J Clin Periodontol 2002: 29: 551–562.
88. Slade GD, Offenbacher S, Beck JD, Heiss G, Pankow JS.
Acute-phase inflammatory response to periodontal dis-
ease in the US population. J Dent Res 2000: 79: 49–57.
89. Smith SC. Current and future directions of cardiovascular
risk prediction. Am J Cardiol 2006: 97(Suppl.): 28A–32A.
90. Smith JD, Trogan E, Ginsberg M, Grigaux C, Tian J, Miyata
M. Decreased atherosclerosis in mice deficient in both
macrophage colony-stimulating factor (op) and apolipo-
protein E. Proc Natl Acad Sci U S A 1995: 92: 8264–8268.
91. Söder PO, Söder B, Nowak J, Jogestrand T. Early carotid
atherosclerosis in subjects with periodontal diseases.
Stroke 2005: 36: 1195–1200.
92. Sukhova GK, Schonbeck U, Rabkin E, Schoen FJ, Poole AR,
Billinghurst RC, Libby P. Evidence for increased colla-
genolysis by interstitial collagenases-1 and -3 in vulner-
able human atheromatous plaques. Circulation 1999: 99:
2503–2509.
93. Taylor AJ, Kent SM, Flaherty PJ, Coyle LC, Markwood TT,
Vernalis MN. ARBITER: Arterial Biology for the Investi-
gation of the Treatment Effects of Reducing Cholesterol: a
126
randomized trial comparing the effects of atorvastatin and
pravastatin on carotid intima medial thickness. Circula-
tion 2002: 106: 2055–2060.
94. Tuzcu EM, Kapadia SR, Tutar E, Ziada KM, Hobbs RE,
McCarthy PM, Young JB, Nissen SE. High prevalence of
coronary atherosclerosis in asymptomatic teenagers and
young adults: evidence from intravascular ultrasound.
Circulation 2001: 103: 2705–2710.
95. Umino M, Nagao M. Systemic diseases in elderly dental
patients. Int Dent J 1993: 43: 213–218.
96. van de Ree MA, Huisman MV, Princen HM, Meinders
AE, Kluft C. Strong decrease of high sensitivity
C-reactive protein with high-dose atorvastatin in
patients with type 2 diabetes mellitus. Atherosclerosis
2003: 166: 129–135.
97. Verma S, Wang CH, Li SH, Dumont AS, Fedak PW, Badi-
walam MV, Dhillon B, Weisel RD Li RK, Mickle DA,
Stewart DJ. A self-fulfilling prophecy C-reactive protein
attenuates nitric oxide production and inhibits angio-
genesis. Circulation 2002: 106: 913–919.
98. Vettore MV. Periodontal disease and cardiovascular dis-
ease. Evid Based Dent 2004: 5: 69.
99. Virmani R, Robinowitz M, Geer JC, Breslin PP, Beyer JC,
McAllister HA. Coronary artery atherosclerosis revisited in
Korean war combat casualties. Arch Pathol Lab Med 1987:
111: 972–976.
100. World Health Organization. The World Health Report
1997. Geneva: World Health Organization, 1997.
101. Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP, Sempos
CT. An examination of the relation between periodontal
health status and cardiovascular risk factors. Serum total
and HDL cholesterol, C-reactive protein, and plasma
fibrinogen. Am J Epidemiol 2000: 85: 180–189.
102. Zwaka TP, Hombach V, Torzewski J. C-reactive protein-
mediated low density lipoprotein uptake by macrophages
implications for atherosclerosis. Circulation 2001: 103:
1194–1197.