cardiovascular disease, inflammation, and periodontal infection
TRANSCRIPT
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
Cardiovascular disease, inflammation, and periodontal infection
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nu
mb
er
of
tee
th
an
dh
isto
ryo
fp
eri
od
on
tal
dis
ea
se
Fa
tal
an
dn
on
-fa
tal
my
oc
ard
ial
infa
rcti
on
or
sud
de
nd
ea
th(r
ev
asc
u
lari
zati
on
ca
ses
exc
lud
ed
)
Asm
all
ass
oc
iati
on
be
twe
en
too
thlo
ssa
nd
co
ron
ary
he
art
dis
ea
seri
skfo
rm
en
(RR
1.7
)
118
Paquette et al.
Ta
ble
2.
Co
nti
nu
ed
Re
fere
nc
eS
tud
yd
esi
gn
Po
pu
lati
on
Pe
rio
do
nta
lo
utc
om
e
or
ex
po
sure
Ca
rdio
va
scu
lar
ou
tco
me
Fin
din
gs
an
dc
on
clu
sio
ns
Wu
et
al.
(10
1)
Co
ho
rt9
,96
2su
bje
cts
(NH
AN
ES
I
an
dfo
llo
w-u
p)
Su
bje
cts
cla
ssifi
ed
wit
hn
o
pe
rio
do
nta
ld
ise
ase
,w
ith
gin
giv
itis
,p
eri
od
on
titi
s
(‡4
tee
thw
ith
ov
ert
po
ck
eti
ng
)o
re
de
ntu
lou
s
Inc
ide
nt
ca
ses
of
stro
ke
Co
mp
are
dto
pe
rio
do
nta
l
he
alt
h,
rela
tiv
eri
skfo
rst
rok
e
wit
hp
eri
od
on
titi
sw
as
2.1
an
d
sig
nifi
ca
nt
Be
ck
et
al.
(8)
Co
ho
rt6
,01
7su
bje
cts
(AR
ICS
tud
y)
Se
ve
rep
eri
od
on
titi
sd
efi
ne
da
s
cli
nic
al
att
ac
hm
en
tlo
ss
‡3m
ma
t‡3
0%
of
site
s
Ca
roti
da
rte
ryin
tim
a-
me
dia
wa
llth
ick
ne
ss
‡1m
m
Pe
rio
do
nti
tis
ma
yin
flu
en
ce
ath
ero
ma
form
ati
on
(OR
1.3
)
Hu
joe
le
ta
l.(4
4)
Co
ho
rt8
,03
2d
en
tate
ad
ult
s(N
HA
NE
SI)
Pe
rio
do
nta
lp
oc
ke
tin
ga
nd
att
ac
hm
en
tlo
ss
De
ath
or
ho
spit
ali
zati
on
du
eto
co
ron
ary
he
art
dis
ea
seo
rre
va
scu
lari
za-
tio
no
bta
ine
dfr
om
me
dic
al
rec
ord
s
Pe
rio
do
nti
tis
wa
sn
ot
ass
oc
iate
dw
ith
asi
gn
ific
an
t
inc
rea
sed
risk
for
co
ron
ary
he
art
dis
ea
se
Ho
we
lle
ta
l.(4
3)
Co
ho
rt2
2,0
37
ma
lesu
bje
cts
(Ph
ysi
cia
n’s
He
alt
h
Stu
dy
I)
Se
lf-r
ep
ort
ed
pre
sen
ce
or
ab
sen
ce
of
pe
rio
do
nta
l
dis
ea
sea
tb
ase
lin
e
Inc
ide
nt
fata
la
nd
no
n-
fata
lm
yo
ca
rdia
l
infa
rcti
on
or
stro
ke
No
sig
nifi
ca
nt
ass
oc
iati
on
be
twe
en
self
-re
po
rte
d
pe
rio
do
nta
ld
ise
ase
an
d
ca
rdio
va
scu
lar
dis
ea
see
ve
nts
Hu
ng
et
al.
(45
)C
oh
ort
41
,40
7m
en
fro
mth
e
HP
FS
an
d5
8,9
74
wo
me
nfr
om
the
NH
S
Se
lf-r
ep
ort
ed
too
thlo
ssa
t
ba
seli
ne
Inc
ide
nt
fata
la
nd
no
n-
fata
lm
yo
ca
rdia
l
infa
rcti
on
or
stro
ke
Fo
rm
en
wit
hto
oth
loss
,th
e
rela
tiv
eri
skfo
rc
oro
na
ry
he
art
dis
ea
sew
as
1.3
6.
Fo
r
wo
me
nw
ith
too
thlo
ss,
the
rela
tiv
eri
skw
as
1.6
4
Pu
ssin
en
et
al.
(73
)C
oh
ort
6,9
50
Fin
nis
hsu
bje
cts
inth
eM
ob
ile
Cli
nic
He
alt
hS
urv
ey
Se
rum
an
tib
od
ies
to
P.
gin
giv
ali
so
r
A.
act
ino
myc
etem
com
ita
ns
Inc
ide
nt
fata
lo
rn
on
-fa
tal
stro
ke
Se
rop
osi
tiv
esu
bje
cts
ha
da
n
OR
of
2.6
for
stro
ke
Be
ck
et
al.
(9)
Co
ho
rt1
5,7
92
sub
jec
ts(A
RIC
Stu
dy
)
Se
rum
an
tib
od
ies
to
pe
rio
do
nta
lp
ath
og
en
s
Ca
roti
da
rte
ry
inti
ma
-me
dia
wa
ll
thic
kn
ess
‡1m
m
Pre
sen
ce
of
an
tib
od
yto
C.
rect
us
wa
sa
sso
cia
ted
wit
h
ca
roti
da
the
rosc
lero
sis
(OR
2.3
)
En
ge
bre
tso
ne
ta
l.(2
9)
Co
ho
rt2
03
sub
jec
tsfr
om
INV
ES
T
Ra
dio
gra
ph
ica
lve
ola
rb
on
e
loss
Ca
roti
dp
laq
ue
thic
kn
ess
via
ult
raso
no
gra
ph
y
Se
ve
rep
eri
od
on
tal
bo
ne
loss
wa
sin
de
pe
nd
en
tly
ass
oc
iate
d
wit
hc
aro
tid
ath
ero
scle
rosi
s
(OR
3.6
4)
119
Cardiovascular disease, inflammation, and periodontal infection
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
eS
tud
yd
esi
gn
Po
pu
lati
on
Pe
rio
do
nta
lo
utc
om
e
or
ex
po
sure
Ca
rdio
va
scu
lar
ou
tco
me
Fin
din
gs
an
dc
on
clu
sio
ns
De
sva
rie
ux
et
al.
(25
)C
oh
ort
1,0
56
sub
jec
tsfr
om
INV
ES
T
Su
bg
ing
iva
lb
ac
teri
al
bu
rde
nC
aro
tid
art
ery
inti
ma
-me
dia
wa
ll
thic
kn
ess
‡1m
m
Se
ve
rep
eri
od
on
tal
bo
ne
loss
wa
sin
de
pe
nd
en
tly
ass
oc
iate
d
wit
hc
aro
tid
ath
ero
scle
rosi
s
(OR
3.6
4)
Ab
ne
te
ta
l.(1
)C
oh
ort
29
,58
4ru
ral
Ch
ine
se
sub
jec
ts
To
oth
loss
Inc
ide
nc
eo
ffa
tal
my
oc
ard
ial
infa
rcti
on
or
stro
ke
To
oth
loss
wa
sa
sso
cia
ted
wit
h
an
inc
rea
sed
od
ds
for
de
ath
fro
mm
yo
ca
rdia
lin
farc
tio
n
(RR
1.2
9)
an
dst
rok
e(R
R1
.12
)
EC
G,
ele
ctr
oc
ard
iog
ram
;O
R,
od
ds
rati
o;
RR
,re
lati
ve
risk
.M
od
ifie
dfr
om
Re
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
Cardiovascular disease, inflammation, and periodontal infection
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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