Cardiovascular disease, inflammation, and periodontal infection

Cardiovascular disease,inflammation, and periodontalinfection

DA V I D W. PA Q U E T T E, NA D I N E BR O D A L A & TI M O T H Y C. NI 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

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 thepathogenesis of cardiovasculardisease

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

Periodontology 2000, Vol. 44, 2007, 113–126

Printed in Singapore. All rights reserved

� 2007 The Authors.

Journal compilation � 2007 Blackwell Munksgaard

PERIODONTOLOGY 2000

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

Table 1. Summary of inflammatory signals and events in atherogenesis. Modified from Ref. (58)

Stages of

atherogenesis

Endothelial

expression of

adhesion molecules

Development of fatty

streak

Progression to

complex plaque

Plaque rupture

Cellular and

vascular

changes

• Endothelial

permeability

• Rolling and

binding of

monocytes to

endothelial cells

• Diapedesis and

migration of

monocytes from the

vessel lumen to

intima

• Maturation to

macrophages

• Accumulation of

cholesterol esters

and transformation

to foam cells

• Smooth muscle

migration from

media to intima

• Production and

accumulation of fibrous

tissue in the intima

(fibro-lipid lesion)

• Formation of

fibrous cap and

necrotic core

• Physical disruption

of atherosclerotic

lesion

• Thinning and

fracture of fibrous

cap

• Thrombus formation

Inflammatory

signals or

events

Vascular adhesion

molecule-1 promoted

by oxidized lipids,

interleukin-1, tumor

necrosis factor-a,

disrupted blood flow,

activation of nuclear

factor-jB pathways

and reduction in nitric

oxide

Monocyte

chemoattractant

protein-1

and macrophage

colony-stimulating

factor

Platelet-derived growth

factor, transforming

growth factor-b,

interleukin-1,

interleukin-6,

tumor necrosis factor-a,

macrophage colony-

stimulating

factor, monocyte

chemoattractant protein-1

and CD40

Matrix metalloproteinases

1, 8 and 13 promoted

by interleukin-1,

CD40 ligand and

interfeuron-c

114

Paquette et al.

atherosclerotic lesion called the �fatty streak.� 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 �foam cells�(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 �complex plaque.� 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

Cardiovascular disease, inflammation, and periodontal infection

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 �fibrous cap� 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 forcardiovascular disease

Traditional major risk factors for cardiovascular dis-

ease include cigarette smoking, hypertension (>140/

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 Physicians� Health Study, an epidemio-

logical study of over 22,000 healthy middle-aged men

116

Paquette et al.

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 periodontaland 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, �Does periodontal

disease influence the initiation/progression of

atherosclerosis and therefore cardiovascular disease,

stroke, and peripheral vascular disease?� 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, �Periodontal disease may

be modestly associated with atherosclerosis, myo-

cardial infarction, and cardiovascular events.� An

accompanying consensus report approved by the

American Academy of Periodontology recommends,

�Patients and health care providers should be in-

formed that periodontal intervention may prevent

the onset or progression of atherosclerosis-induced

diseases.�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


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118

Paquette et al.

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119


Recent findings from several worldwide population

studies warrant detailed consideration. These studies

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-

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

clinical coronary heart disease (myocardial infarction

or revascularization procedure) and subclinical

atherosclerosis (carotid artery intima-media wall

thickness using B-mode ultrasound) as dependent

variables in the population. Individuals with both

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

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

logistic regression analysis indicated a significant

association between severe periodontitis and thick-

ened carotid arties after adjusting for covariates like

age, gender, diabetes, lipids, hypertension, and

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

periodontal organisms using a whole bacterial

checkerboard immunoblotting technique (9). Ana-

lyzing the mean carotid intima-media wall thickness

(‡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–

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

rectus and Peptostreptococcus micros antibody titers

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

smoking indicated that all microbial models signifi-

cant for smokers were also significant for never

smokers except for Porphyromonas gingivalis. Thus,

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

Ta

ble

2.

Co

nti

nu

ed

Re

fere

nc

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yd

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od

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f.(8

1).

120

Paquette et al.

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


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 andexperimental 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-

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

�complete mouth disinfection� (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

122

Paquette et al.

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.

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Health & Medicine

Cardiovascular disease, inflammation, and periodontal infection