Atherosclerosis 241 (2015) 555e560

Contents lists available at ScienceDirect

Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Review

Interaction between periodontal disease and atherosclerotic vascular

disease e Fact or fiction?
€ rg Eberhard b, Daniel R. Reissmann a, Guido Heydecke a, Udo Seedorf a, *
Ghazal Aarabi a, Jo
a
Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-Eppendorf, Martinistrasse 52,
20246 Hamburg, Germany
b
Periimplant and Oral Infections, Department of Prosthetic Dentistry and Biomaterial Sciences, Hannover Medical School, Carl-Neuberg-Strasse 1, 30625
Hannover, Germany

a r t i c l e i n f o a b s t r a c t

Article history: C-reactive protein (CRP) level is associated with the 10-year risk of an atherosclerotic vascular disease
Received 22 January 2015 (ASVD), suggesting presence of systemic inflammation probably long before ASVD is present. Where,
Received in revised form however, does this systemic inflammation come from? One active area of research has been the study of
22 April 2015
dental infection and various forms of periodontal disease (PD), both of which are highly prevalent in
Accepted 30 April 2015
Available online 5 May 2015
populations at risk for ASVD. Recent data show that ASVD and PD interact with each other via systemic
release of specific pro- and anti-inflammatory cytokines, small signal molecules and enzymes which
modulate initiation and progression of the chronic inflammatory reaction involved in both diseases. In
Keywords:
CHD risk
addition, periodontal pathogens were identified within atherosclerotic lesions and thrombi isolated from
Stroke risk myocardial infarction patients. LDL cholesterol, a strong risk factor for ASVD, is also associated with PD;
Myocardial infarction and statins, used to treat ASVD, are also active to prevent or reduce PD. Finally, there is growing evidence
Periodontal disease for common genetic susceptibility factors involved in both diseases. These findings support common-
Chronic inflammation alities with respect to the pathogenic mechanisms involved in both inflammatory diseases. Conversely, a
Epidemiology causative relationship cannot yet be concluded in the absence of data from large longitudinal cohort and
Genetic predisposition randomized controlled intervention trials.
© 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Periodontal disease (PD) is a highly prevalent chronic inflam-
matory disease affecting the tooth-supporting structures [1], and
atherosclerotic vascular disease (ASVD) is a highly prevalent
chronic inflammatory condition affecting arterial blood vessels
[2,3]. ASVD is the leading cause of morbidity and mortality in
industrialized countries and is among the major causes of death
worldwide [4]. In the US, ASVD accounts for about 40% of all deaths
each year; over 700,000 people die each year from ASVD (the vast
majority from heart disease and stroke) [5]. ASVD includes “hard”
or major events, like coronary death, myocardial infarction (MI),
death due to cerebrovascular disease and stroke, as well as “soft”
outcomes, such as angina pectoris, revascularization and peripheral
vascular disease, which are not so life threatening [2]. The tradi-
tional risk factors for ASVD have been established based on large
* Corresponding author.
E-mail address: u.seedorf@uke.de (U. Seedorf).
prospective cohort studies. Widely used risk scores for general
cardiovascular events (i.e. the Framingham and the PROCAM risk
scores) encompass variations of the following sex-specific pre-
dictors: age, diabetes, smoking, treated and untreated systolic
blood pressure, total cholesterol, high-density lipoprotein (HDL)
cholesterol, low density lipoprotein (LDL) cholesterol, triglycerides
and body mass index (BMI) replacing triglycerides in simpler
models, and family history of a major ASVD event (PROCAM) [6,7].
However, these factors explain only about half of all deaths from
ASVD, and almost half of all hard ASVD events occur in patients
without the classic risk factors [7,8]. For instance, about 40% of CHD
deaths occur in people with cholesterol levels that are lower than
the population mean [6,7]. Therefore, identifying additional, so-
called emerging risk factors, which are non-traditional, but may
play major roles in explaining some of the variability in ASVD risk is
a core area of current medical research. In this context, the hy-
pothesis that dental infection plays an important role as risk factor
acting independently of the classic Framingham risk factors is
attractive.
Periodontal diseases are an entity of localized, inflammatory

http://dx.doi.org/10.1016/j.atherosclerosis.2015.04.819
0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.
556 G. Aarabi et al. / Atherosclerosis 241 (2015) 555e560
diseases affecting the epithelial, connective and osseous tissues
surrounding the teeth [9]. According to the most common clas-
sification scheme, introduced by the International Workshop for a
classification of Periodontal Diseases and Conditions in 1999 [10],
eight main subtypes are discriminated. Bacteria once attached to
teeth along the gingival margin grow within minutes to form
biofilms and induce an immune response in the adjacent gingival
tissues. After a few days, clinical abnormalities develop consisting
of swelling, redness and bleeding [11]. If the bacterial biofilm and
accompanying inflammatory reaction migrates apically along the
root surface and affects the tooth supporting structures the
gingival inflammation becomes periodontitis [12]. It is estimated
that in most non-clinical populations 5e20% of the subjects suffer
from severe, generalized periodontitis [13,14]. The World Health
Organization estimates that advanced disease stages with peri-
odontal pockets 6 mm affects 10e15% of all adults around the
world [15].
Could oral infectious agents promote atherogenesis? Consid-
ering the existing diversity of supporting and contradicting evi-
dence, answering this question convincingly and beyond any doubt
seems difficult. Since a better understanding of the relationships
existing between oral infections and atherosclerosis would have
profound implications for risk stratification, disease prevention and
treatment, we considered that it might be of interest to review the
current status of knowledge and discuss some ongoing and future
directions of research in this area. In 2012, Lockhart et al. issued a
scientific statement for the American Heart Association covering
the topic [16]. The most notable conclusions then were: (1)
although observational studies supported an association between
PD and ASVD independent of known confounders, a causative
relationship existing between the two diseases could neither be
supported nor dismissed, and (2) it was unclear whether peri-
odontal interventions could prevent ASVD or modify its outcomes
in the long-term [16]. Since then, many additional studies have
been conducted and results published. Thus, the scope of the pre-
sent review is to focus on potential progress obtained by new work
published after 2012.
1.1. Oral infections and atherosclerosis
Past research showed that atherosclerosis is the result of a
chronic inflammatory process and inflammation is seen to play a
pivotal role in all phases of atherogenesis [recently reviewed in
Ref. [17]]. From a basic perspective, specific cytokines, receptors,
enzymes and adhesion molecules which participate in adaptive
and innate immunity promote the recruitment of monocytes to
the arterial wall, followed by foam cell formation, cellular prolif-
eration of the intima, wall thickening, and ultimately arterial
narrowing. Finally, rupture of the mature plaque can lead to acute
luminal occlusion resulting in a major ASVD event with devas-
tating consequences for the affected organs. From an epidemio-
logic perspective, a wealth of evidence demonstrates that
biomarkers of inflammation are increased among apparently
healthy men and women at risk for future ASVD even when
cholesterol levels are low. The magnitude of the effect is similar as
that of other well established risk factors, such as hypertension,
overweight and hypercholesterolemia [18]. The JUPITER (Justifi-
cation for the Use of Statins in Prevention: an Intervention Trial
Evaluating Rosuvastatin) trial, a randomized placebo-controlled
trial including ~18,000 patients demonstrated that statin ther-
apy reduced risk of myocardial infarction and stroke by more than
40% in individuals with low cholesterol who had increased levels
of C-reactive protein (CRP) [19]. CRP is a pattern recognition
molecule, which participates in the systemic response to inflam-
mation [20]. The protein binds to specific molecular
configurations that are typically exposed during cell death or are
found on the surfaces of pathogens [21]. It is a sensitive non-
specific acute-phase marker for infection and inflammation
regulated by cytokines interleukin-6 (IL-6), interleukin-1b (IL-1b)
and tumor necrosis factor-a (TNF-a) [22].
Based largely on the JUPITER trial, it was suggested that it might
be useful to include CRP and other soluble biomarkers of inflam-
mation in risk prediction of first cardiovascular events, particularly
in individuals who have low cholesterol levels and thus are mostly
at intermediate risk for ASVD according to standard risk scores
[23e28]. In 2012, the Emerging Risk Factors Collaboration presented
data showing improvements in the prediction of a first ASVD event
when the concentration of circulating CRP was added as additional
risk factor to standard risk scores [18]. From the presently available
evidence it can be concluded that oral infections including gingivitis
and chronic and aggressive periodontitis consistently elevate sys-
temic levels of CRP. One of the earliest studies was conducted by
Boucher et al. [29], who demonstrated that the highest incidence of
positive CRP tests and the strongest CRP test reactions were present
in patients with acute alveolar abscesses. Subsequently, various
studies showed that patients with less severe PD such as chronic
periodontitis also have increased serum levels of CRP relative to
unaffected subjects [30e33]. The level of infection with periodontal
pathogens is positively correlated with CRP level [34,35], and the
extent of CRP elevation seems to be pathogen-specific: Porphyr-
omonas gingivalis induces pronounced CRP increases whereas
Aggregatibacter actinomycetecomitans is less active [35,36].
It is conceivable that systemically elevated CRP, accompanied by
increases of other inflammatory mediators, may increase inflam-
matory activity in existing atherosclerotic lesions, thereby
increasing the risk of an ASVD event (Table 1). Chen et al. [37]
showed that platelet-activating factor (PAF), a potent pro-
inflammatory mediator, was almost fivefold elevated in serum
from patients with PD compared with healthy controls. Patients
who had only PD or only CHD and those who had CHD together
with PD all showed similarly elevated PAF levels, indicating that
one of the two conditions is sufficient to fully release the PAF
response. This observation together with the fact that PD usually
has an earlier onset than ASVD suggests that systemic PD-induced
PAF elevations may play a pro-inflammatory role early on in
atherogenesis rather than in the later steps, which are typically
involved in CHD. Likewise, presence of CHD may have a stimulatory
effect on the course of PD via CHD-mediated PAF elevations. This
and a number of other studies support that ASVD and PD do in fact
have a two-way relationship by interacting with each other via
systemic release of specific pro- and anti-inflammatory cytokines,
small signal molecules, such as eicosanoid inflammatory mediators
and shingosine-1-phosphate (S1P), and enzymes which modulate
initiation and progression of the chronic inflammatory reaction
involved in both diseases (Fig. 1).
1.2. Two-way relationship e potential mechanisms
Infections of remote origin may initiate and promote systemic
inflammatory reactions by several mechanisms, all of which have
been verified in animal or human studies. These mechanisms
include (A) the local production of inflammatory mediators in
inflamed gingival or periodontal tissues elevating the systemic
inflammatory burden and (B) the release of pathogenic bacteria
from periodontal affected tissues into the vascular system, either
by direct release into the circulation or as internalized particles
of immune cells via the lymphatic or blood system. Over the last
decades isolated steps of these pathways or singular experi-
mental components have been investigated mostly in animal
models, however, the entire mechanisms have not been
 G. Aarabi et al. / Atherosclerosis 241 (2015) 555e560 557

Table 1 peripheral blood has been demonstrated [42].

Common cytokines involved in the pathogenesis of atherosclerotic vascular
disease and periodontal disease.
Family Cytokine
Immunoregulatory IFN-g, IL-2, IL-4, IL-5, IL-7
Pro-inflammatory IL-1a, IL-1b, TNFa, IL-6, PAF
Anti-inflammatory IL-1Ra, IL-4, IL-10
Growth factor PDGF, EGF, FGF, IGF, VEGF
Chemotactic IL-8, MIP-1, MCP-1, RANTES
EGF, epidermal growth factor; FGF, fibroblast growth factor; IFN, interferon; IGF
insulin-like growth factor; IL, interleukin; IL-1Ra, interleukin-1-receptor
antagonist; MIP, macrophage inflammatory protein; MCP, monocyte chemo-
tactic protein; PAF, platelet activating factor; PDGF, platelet derived growth
factor; RANTES, regulated upon activation, normal T cell expressed and
secreted; VEGF, vascular endothelial growth factor.
elucidated yet.
Bacteria are first inoculated into the child's oral cavity by the
parents, growing to a complex ecosystem harboring approximately
700 different bacterial species, which populate all oral hard and soft
surfaces [11]. Gingivitis is a general precursor of periodontitis and
although differences exist between these two periodontal diseases
regarding the composition of the biofilms, pathological processes
and composition of infiltrating immune cells both are basically
bacterially induced inflammatory diseases with a long-standing
chronic character. In gingivitis, epithelial cells are the first line of
defense building a mechanical and chemical defense shield, aimed
to target bacteria by the release of antimicrobial peptides hBD-2,
hBD-3 and the cathelicidin LL-37, as well as by initiating immune
cell migration by the release of chemoattractans, e.g. IL-1 or IL-8
[38e40]. Infiltrating monocytes release additional proin-
flammatory mediators and contribute to elevated concentrations of
these compounds in the soft tissues, which has been documented
many times during gingivitis and periodontitis compared to
healthy controls. The edematous swelling and high bleeding ten-
dency of the gingival and periodontal tissues facilitates the trans-
mission of these compounds into the bloodstream and it is possible
to measure increased concentrations of the mediators after
experimental and natural gingival lesions as well as in subjects
suffering from periodontitis in peripheral blood [41]. Even in
intervention studies the causal relationship between oral inflam-
matory processes and the concentration of compounds in
Bacterial DNA of oral origin has been frequently detected in
atherosclerotic lesions suggesting that bacteria may affect athero-
genesis and other systemic pathological conditions directly [43].
Transient bacteremias were shown in patients with PD after tooth
brushing and following periodontal treatment [44e46]. Direct
spreading of oral bacteria via blood and/or lymph is considered to
be the main mechanism how these bacteria reach the arterial wall.
In addition, they may get trapped within the arterial wall together
with phagocytic cells [45,47]. Several studies have identified high
levels of periodontopathogens such as P. gingivalis and Treponema
denticola in atherosclerotic lesions [48e50]. In contrast, biopsies
taken from non-atherosclerotic aortic tissue provided mostly only
signals around the detection limit for these bacteria using poly-
merase chain reaction (PCR) [51]. In vitro studies and in vivo animal
studies have shown that bacteria associated with periodontal dis-
ease, such as P. gingivalis, may contribute to vascular inflammation
by several mechanisms such as activation of Toll-like receptors,
increasing the production of pro-inflammatory mediators, and the
expression of cell-surface adhesion molecules, causing apoptosis of
vascular cells, and triggering of the coagulation cascade [47,52].
Using quantitative polymerase chain reaction (PCR), it could be
demonstrated that bacterial DNA of periopathogens accounted for
47.3% of the total bacterial DNA found in atheromatous samples
from patients with PD. In contrast, only 7.2% of the total bacterial
DNA detected in atheromas from periodontally healthy subjects
was from periopathogenic species [53]. Ott et al. detected more
than 50 bacterial species in coronary atherosclerotic samples [54].
These and other studies suggest that a multitude of bacterial spe-
cies may contribute to the pathogenesis of atherosclerosis [55e57].
It is interesting to note that the detection of bacteria associated
with the oral cavity is not limited to pathogens associated with
severe states of oral diseases, like P. gingivalis, but was also reported
for bacteria that are associated generally speaking with increased
amounts of dental plaque on tooth surfaces, like streptococci [58].
1.3. Lessons from animal models
Animal models are particularly suited to unravel mechanisms
involved in complex interactions, which might exist between ASVD
and PD, because they can be kept in a controlled environment. A

Fig. 1. Two-way relationship between atherosclerotic vascular disease and periodontal disease. Atherosclerosis and chronic gum inflammation (periodontitis, induced by bacterial
biofilm) cause a localized cytokine response. Interaction between atherosclerotic vascular disease and periodontal disease is mediated via systemic release of these locally produced
pro- and anti-inflammatory cytokines and small signal molecules, such as platelet activating factor, eicosanoid inflammatory mediators and shingosine-1-phosphate. Proin-
flammatory cytokines (IL-1b, IL-6, TNFa) induce production of C-reactive protein and fibrinogen in the liver, which lead to an acute phase response promoting atherogenesis and
periodontitis. Oral pathogens entering the body via blood and lymph may get trapped at atherosclerotic lesion sites, thus providing a second inflammatory stimulus and inducing
atheroma formation and thrombosis. Risk factors shared between both diseases (metabolic syndrome, cigarette smoking, obesity, diabetes, genetic predisposition) are also thought
to be related to increased systemic inflammation. Abbreviations: CRP, C-reactive protein; IL, interleukin; IFN, interferon; MCP, monocyte chemoattractant protein; PAF, platelet
activating factor; PDGF, platelet-derived growth factor; RANTES, regulated on activation, normal T cell expressed and secreted; S1P, sphingosine-1-phosphate; TNF, tumor necrosis
factor; VEGF, vascular endothelial growth factor.
558 G. Aarabi et al. / Atherosclerosis 241 (2015) 555e560
well-established animal model of atherosclerosis is the hypercho-
lesterolemic apolipoprotein-E knockout (apo E null) mouse. It could
be demonstrated that oral infection of cholesterol-fed apo E null
mice with P. gingivalis, the etiological agent of human PD, led to
accelerated plaque accumulation in the aortic sinus of homozygous
and heterozygous mice [62,63]. Similar studies on the innominate
artery of apo E null mice showed that oral infection with P. gingivalis
was associated with a pronounced early increase of lipid accumu-
lation, macrophages and T-cells. The lesions exhibited many fea-
tures of human atherosclerotic disease including plaque rupture
which could be prevented by immunization with heat-killed
P. gingivalis prior to the infection [64]. Chronic oral exposition (up
to 24 weeks) of normal chow-fed apo E null mice to P. gingivalis led
to a strong inflammatory aortic Th2 response, increased number
and size of atherosclerotic lesions, a significant increase of oral
bone resorption, and viable bacteria in oral epithelium and in the
aorta [65]. In other experiments, C57BL/6J mice were made obese by
feeding them with a high-fat diet followed by infection with
P. gingivalis. It could be demonstrated that the obese mice reacted to
infection with more pronounced endothelial injury compared with
lean controls and more P. gingivalis bacteria were detected deep in
the smooth muscle of the aorta from obese mice [66].
In addition to mouse models, also non-human primates have
been used to study relationships between PD or gingivitis and
atherosclerosis in vivo. Besides systemic translocation of bacteria
and their products and increases of systemic inflammatory bio-
markers, PD-mediated alterations of serum lipids and lipoproteins
which were consistent with a higher atherogenic risk were
demonstrated [67]. In rhesus monkeys, it was shown that monkeys
with a condition resembling human metabolic syndrome had a
much higher prevalence of PD compared with controls. PD was
linked to an app. twofold increase in serum CRP observed in
monkeys with metabolic syndrome [68].
1.4. Intervention studies with statins
Whether patients with familial hypercholesterolemia or other
genetically determined forms of hypercholesterolemia are more
prone to PD than normal subjects is currently unclear. According to
recently published data from the global STABILITY trial (comprising
15,828 participants with stable CHD), tooth loss (self-reported,
used as indicator of PD) was positively associated with glucose
level, LDL cholesterol, systolic blood pressure, waist circumference
and hs-CRP. Gum bleeding was associated with LDL cholesterol
level and systolic blood pressure. Self-reported indicators of PD
were common in the chronic CHD population and were associated
with an increasing socioeconomic and CVD risk factor burden [80].
These results are in line with earlier data published by Katz et al.
[81]. Based on a large cohort study with data on over 10,000 Israeli
military service men and women, the presence of periodontal
pockets as measured by the Community Periodontal Index of
Treatment Needs (CPITN) was positively associated with total
cholesterol and LDL-cholesterol after adjustments for body mass
index (BMI), age, diastolic blood pressure, and smoking in men but
not in women. There are a number of smaller studies showing
similar results and, based on these findings; it seems highly likely
that hypercholesterolemia is a risk factor not only for ASVD but also
for PD.
Lowering LDL cholesterol by statins reduces cardiovascular event
risk and several recent studies indicated similarly beneficial effects of
statins on the periodontal status in hyperlipidemic patients [82e87].
In this respect, it seems interesting to us, that amorphic cholesterol
deposits are known to be frequently present adjacent to the
degraded bone area of the tooth supporting tissues in PD [88,89]. It
was proposed that these cholesterol deposits uphold the chronic
inflammatory reaction via continuous recruitment of macrophages
and giant cells and activation of the inflammasome [90,91].
2. Discussion
The oral inflammatory hypothesis of atherosclerosis in its orig-
inal version assumed that periodontal pathogens, which enter the
body via the injured oral epithelium, are trapped at the site of the
atherosclerotic lesion and lead to a more vulnerable plaque [59].
Although a contribution of such direct pathogen involvement
cannot be ruled out, it seems likely that complex interactions be-
tween the two chronic inflammatory diseases are involved in both
diseases as well. These interactions are likely mediated by systemic
release of specific pro- and anti-inflammatory cytokines, small
signal molecules, and enzymes which act as signals modulating
initiation and progression of the chronic inflammatory reaction
(Fig. 1). Additionally, pro-thrombotic effects are likely associated
with the chronic periodontal infection which may promote acute
ASVD events (i.e. myocardial infarction and cerebrovascular events)
[92].
ASVD and PD have many common etiological, epidemiological
and genetic features. These include a large set of overlapping risk
factors [6,96,97], common genetic susceptibility variants [98e100],
and commonly affected biomarkers [101]. These commonalities
may provide an explanation for the observed association between
both diseases. On the other hand, an important independent
contribution and causal role of oral infectious disease for ASVD
cannot be ruled out at present. A better understanding of the
seemingly complex relationships existing between both diseases
could potentially result in improved risk stratification, disease
prevention and treatment.
Periodontitis is treatable and preventable. Recent intervention
trials have demonstrated that the treatment of PD by various
means, including intensive mechanical therapy, antibiotic therapy
and extraction, can lower serum CRP levels. D'Aiuto et al. [93]
observed for instance a 0.5 mg/l median decrease of serum CRP 6
months after completion of therapy. On the other hand, others
failed to observe such positive effects [94]. A recently published
meta-analysis demonstrated that periodontal treatment improved
endothelial function, reduced ASVD biomarkers and led to a less
atherogenic lipid profile, especially in patients already suffering
from ASVD and/or diabetes [95]. In addition, results from recent
studies showed that intervention with statins has beneficial effects
not only on ASVD but also on PD. It is however currently unclear
whether the statin effect on PD results from LDL cholesterol
lowering or rather from some of the anti-inflammatory, so-called
pleiotropic, effects, known to result from HMG-CoA reductase in-
hibition. It should also be noted that the evidence comes mostly
from observational studies and the statin-treated patient groups
may have had an advantage due to concomitant administration of
other drugs or another medical attention bias.
Ultimately, the oral inflammatory hypothesis of atherosclerosis
will need direct testing in large longitudinal cohort studies to un-
cover cause-effect-relationships and to allow risk quantitation. In
addition, randomized controlled trials demonstrating that anti-
inflammatory treatments targeting oral inflammations and long-
term improved oral hygiene can reduce vascular event rates are
clearly needed. Moreover, the importance of oral inflammation
relative to other disorders associated with systemic inflammation
(i.e. psoriasis and rheumatoid arthritis) should be investigated.
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