Current Oral Health Reports

https://doi.org/10.1007/s40496-018-0165-3

SYSTEMIC DISEASES (N BUDUNELI, SECTION EDITOR)

Cardiovascular Diseases and Periodontal Disease

Thomas T. Nguyen 1 & Kevin Y. Wu 2 & Maude Leclerc 1 & Hieu M. Pham 2 & Simon D. Tran 2

# Springer International Publishing AG, part of Springer Nature 2018

Abstract
Purpose of Review Periodontitis and cardiovascular diseases are both inflammatory conditions. Recent epidemiological studies
have associated the effects of periodontitis on cardiovascular disease (CVD) progression. This review aims to summarize the
relationship between those two conditions.
Recent Findings Although there is no evidence of a causal relationship, an association between the two conditions is apparent.
The potential factors include bacterial pathway, inflammation, and genetics. Periodontal bacteria affect endothelial cells through
interactions that aggravate the atherogenic process. Ulcerated periodontium produces cytokines which increase the production of
acute-phase proteins that have been associated with cardiovascular events. Genetic studies have demonstrated the presence of risk
alleles in the genes ANRIL and CAMTA1/VAMP3 that are shared between these two diseases.
Summary This review discusses the current understanding of CVD pathogenesis, underlying mechanisms of periodontitis in
CVD, and effects of periodontal therapy on CVD, and provides guidelines for treating patients with CVD risks in respect to
periodontal disease.

Keywords Periodontal disease . Cardiovascular disease . Periodontitis . Atherosclerosis . Inflammation . Clinical guidelines

Introduction Periodontal disease is defined as a chronic oral inflamma-

Cardiovascular disease (CVD) amongst other malevolent dis-
eases is the main cause of mortality, claiming 31% of all
deaths worldwide [1]. With a disease of such high severity,
it is necessary to identify any associations that may promote
the initiation and progression of the disease. Cardiovascular
disease encompasses a broad array of conditions that hinder
the physiological function of the heart and/or blood vessels.
Often, the onset of CVD events is initiated by the presence of
atherosclerosis—a condition in which plaque (atheroma) ac-
cumulates within the arteries as a result of an inflammatory
and immune response to endothelial damage [2, 3•].
Escalation of atherosclerosis (also known as arteriosclerotic
vascular disease) can cause thromboembolisms which can
eventually lead to an infarction and/or stroke [2].
This article is part of the Topical Collection on Systemic Diseases
* Thomas T. Nguyen
thomas.thong.nguyen@umontreal.ca
1
Faculty of Dentistry, University of Montreal, Montreal, QC, Canada
2
Faculty of Dentistry, McGill University, Montreal, QC, Canada
tory disease, induced by the local infiltration and accumula-
tion of oral bacteria. The form of periodontal disease of inter-
est is periodontitis—a condition that leads to irreversible dam-
age to the supporting structures of teeth [4–6]. This condition
is highly prevalent as it affects 20–50% of the general popu-
lation [6]. Additionally, periodontitis is known to be associat-
ed with several systemic conditions including diabetes and
CVD. Lockhart et al., an American Heart Association
(AHA) group, stated that though there is a lack of evidence
for a causal relationship between periodontitis and CVD, there
is certainly an association independent to known confounders
[7]. CVD and periodontitis exhibit many common character-
istics: they are multifactorial inflammatory conditions, sharing
confounding factors such as smoking, obesity, and type 2
diabetes. Therefore, it is not unexpected that the key link be-
tween the two diseases is the consequence of inflammation on
the development of the diseases [5, 8, 9]. A proposed mecha-
nism for this association is that patients with periodontitis
have increased susceptibility to the entry of oral bacteria
and/or bacterial components into their bloodstream due to
inflamed and ulcerated subgingival epithelium; the systemic
invasion can lead to an increased risk and progression of CVD
[5].

With the high prevalence rate of CVD and periodontitis, it
is likely that many lives are being burdened; thus, this associ-
ation is a high-priority topic to investigate. This review aims to
raise awareness of the relevance of periodontal disease in the
progression of cardiovascular disease by discussing the cur-
rent understanding of CVD pathogenesis, highlighting the
possible underlying mechanisms of periodontitis in athero-
sclerotic cardiovascular disease, examining the effects of peri-
odontal therapy on atherosclerotic cardiovascular disease, and
providing general guidelines for treating patients with CVD
risks in respect to periodontal disease.
Overview of Atherosclerotic Cardiovascular Disease
(ACVD) Pathology
Atherosclerosis is initiated by damage to vessel endothelium.
Destruction of the vessel induces a cascading effect mediated
by endothelial proinflammatory signals; these signals initiate
smooth muscle cell proliferation and endothelial cell apopto-
sis. Additionally, these signals also upregulate both adhesion
molecule expression (intercellular adhesion molecule
(ICAM)-1, vascular cell adhesion molecule (VCAM)-1, E-
selectin, P-selectin) and chemoattractants (interleukin (IL)-8,
thrombin) leading to diapedesis and accumulation of platelet
and leukocytes [5, 9]. Migrated leukocytes further release pro-
inflammatory cytokines (IL-1, IL-6, tumor necrosis factor
(TNF)-⍺) and release reactive oxygen species (ROS) and pro-
teases that destroy the endothelium extracellular matrix [5, 9].
Low-density lipoproteins (LDLs) accumulate under the intima
layer of the endothelium and are subsequently phagocytized
by macrophages to become foam cells. The formation of foam
cells further increase the release of proinflammatory cytokines
IL-1, IL-6, and TNF-⍺ [2, 9]. Meanwhile, smooth muscle cells
in between the intima and media layer of the vessels secrete
metalloproteinases (MMPs) that promote myogenesis [10];
this causes fibrosis and the formation of fibrous plaque.
Over time, cholesterol deposits upon the plaque and forms
lipid streaks that can disrupt vascular flow. Rupture of plaque
releases thrombotic factors that initiate coagulation when in
contact with platelets and can cause a thromboembolism.
The Relationship Between Periodontitis and ACVD
As both ACVD and periodontitis are multifactorial condi-
tions, multiple potential pathways have been examined to pro-
vide a better understanding of the relationship between both
diseases (Fig. 1). The main factors are bacterial, inflammatory,
and genetics.
Bacterial
As previously stated, acute- and chronic-systemic inflamma-
tion has been shown to have pro-atherogenic effects. These
Curr Oral Health Rep
effects can be mediated by periodontal bacteria through both
direct interactions (e.g., invading endothelial cells, smooth
muscle cells, leukocytes, platelets) and/or indirectly by induc-
ing cells to release paracrine factors that can hinder cellular
functions. Upon entering the blood system, these periodontal
bacteria can release its components into circulation and inten-
sify the pro-atherogenic responses in endothelial cells.
Specifically, the outer membrane vesicles (gingipains) and
free soluble bacterial components from the bacteria
P o r p h y ro m o n a s g i n g i v a l i s a n d A g g re g a t i b a c t e r
actinomycetemcomitans, respectively, can irritate endothelial
cells causing inflammation [11, 12]. Periodontitis is a segue to
bacteremia—leaving the patient vulnerable to systemic spread
and invasion of oral pathogens in endothelial cells leading to
further complications. In past experimental animal models, it
was reported that inoculation of P. gingivalis promoted
ACVD pathogenesis through inflammation and lipid deposi-
tion in vascular walls [13].
Inflammatory
Production and release of proinflammatory cytokines (tumor
necrosis factor (TNF)-⍺, IL-1, IL-6) and other chemokines
from the ulcerated periodontium cause hepatic production of
acute-phase proteins including but not limited to C-reactive
protein (CRP), fibrinogen, and amyloid A protein [5, 9].
Prolonged bacteremia is detected by the adaptive immune
system; immune cells react by producing antibodies specific
to the intruding periodontal pathogens and its pathogen-
associated molecular patterns (PAMPs). The importance of
this reaction is that it can initiate a cross-reaction between
endothelial cells and oxidized LDL which facilitates the trans-
location of lipids into the intima layer of the vessel wall. The
previously mentioned antibodies and inflammatory cytokines
also induce type 1 T-helper (Th1) responses which recruit
monocytes/macrophages to the atheroma site where the oxi-
dized LDLs are engulfed, thereby forming foam cells and
further propagating atherogenesis [5, 9]. Ramirez et al. found
that untreated chronic moderate to severe periodontitis with
subgingival infection by red complex microorganisms is as-
sociated with systemic inflammation. This case-control study
showed that patients with periodontitis have increased system-
ic levels of E-selectin, myeloperoxidase (MPO), and ICAM-1
when compared to periodontally healthy controls [14].
Notably, MPO is considered a pathogenic factor in atheroscle-
rosis as it tends to be co-present with both inflammatory and
oxidative stress. During these events, it catalyzes the forma-
tion of various ROS and plays a protective role against path-
ogens, including periodontal bacteria [15]. Evidently, recent
studies observing ex vivo models of non-stimulated blood
neutrophils from periodontitis patients demonstrated that
these neutrophils both significantly produced more ROS and
had increased sensitivity to the presence of periodontal
pathogens compared to the control [16]. Furthermore, several
observational studies have also shown an association between
these inflammatory proteins and endothelial dysfunction, ath-
eroma plaque development, and cardiovascular events [17].
Genetics
The genes ANRIL and CAMTA1/VAMP3 contain risk alleles
which contribute to both coronary artery disease (CAD) and
periodontitis [18–20]. Molecular studies provided evidence
for a mechanistic link between CAD, periodontitis, obesity,
and inflammation by placing ANRIL and VAMP3 into regu-
latory network that integrates glucose and fatty acid metabo-
lism with immune response [20, 21]. The impairment of these
pathways by genetic factors may be a common pathogenic
denominator of CAD and periodontitis. In a recent study by
Schaefer et al., they displayed that plasminogen (PLG) is also
a shared genetic risk factor of atherosclerosis and periodontitis
[22]. The PLG-plasmin system plays an important role in the
degradation of tissue barriers and cell migration [23]. Various

pathogenic bacteria were found to bind human PLG on bac-
terial PLG receptors [24, 25], which converts them into pro-
teolytic organisms [26]. Additionally, all known shared risk
genes of CAD and periodontitis are members of the
transforming growth factor-β (TGF-β) signaling pathway.
TGF-β signaling may represent a common site of intersection
between the various downstream pathologies of obesity-
induced complications that comprise CAD and periodontitis.
FURIN and TGFBRAP1 are also good candidate genes pres-
ently under investigation [27].
The Effects of Periodontal Therapy on ACVD
Inflammatory cytokines, particularly TNF-⍺ and IL-6, trigger
an increase in hepatic synthesis and rapid secretion of intra-
vascular plasma proteins, including CRP and fibrinogen [28].
Several studies highlighted a link between periodontitis, var-
ious markers (TNF-⍺, IL-6, CRP, fibrinogen), and a multitude
of systemic changes including dyslipidemia, which are known
risk factors for CVD [29–33]. However, the effect of peri-
odontal treatment on systemic markers of inflammation is still
conflicting. While some studies reported that non-surgical
periodontal treatment of chronic periodontitis did not influ-
ence serum levels of inflammatory markers [34, 35], others
have reported otherwise, finding a significant reduction in
systemic markers of inflammation [33, 36–38].
Current reviews measuring CRP levels highlight mod-
erate support for long-term positive effects of periodontal
treatment on systemic inflammation. In the absence of
systemic inflammation, high sensitivity CRP level of
1 mg/L indicates a lower risk of CVD, while a level of
3 mg/L indicates approximately twice the risk [39]. It is
common for patients to have a transient increase in sys-
temic inflammatory mediators and a decrease in endothe-
lial function following non-surgical periodontal treatment
within a timeframe of 1 month [40]. However, sequential-
ly, these levels will gradually decrease, showing a reduc-
tion in basal CRP levels by 6 months [40]. Recent meta-
analyses report a 0.23- to 0.50-mg/L reduction in CRP
levels of patients with periodontitis 2–6-month post-
periodontal therapy [41, 42, 43•]. A recent randomized
clinical trial revealed that periodontal treatment was effec-
tive in improving the periodontal parameters and reducing
CRP level, erythrocyte sedimentation rate (ESR), and to-
tal cholesterol and triglycerides after 6 months [44•].
Furthermore, patients diagnosed with CVD showed a con-
siderable reduction of CRP from 2.7 ± 1.9 to 1.8 ± 0.9 mg/
L (p < 0.05) at 6 months post-periodontal therapy [45].
Hypercholesterolemia is one of the most important
established risk factors for atherosclerosis. The effect of
periodontal therapy on lipid markers was assessed by
D’Aiuto et al. who observed a significant reduction in
plasma levels of different lipids through periodontal
Curr Oral Health Rep
therapy associated with locally applied minocycline,
6 months after treatment [46]. Conversely, Kamil et al.
observed no significant differences in serum lipid markers
after 3 months of periodontal treatment in patients with
periodontitis and comparatively lower values of LDL at
baseline [47]. It was suggested that the effect of periodon-
tal therapy on LDL seems to be more evident in patients
with higher LDL baseline levels as compared to those
with lower baseline levels [48].
Caula et al. showed a significant reduction in triglycerides
after 2 and 6 months and in total cholesterol after 6 months,
and a tendency for decreased levels of LDL after 6 months of
periodontal treatment in the test group. The non-surgical peri-
odontal treatment was effective in reducing the levels of sys-
temic inflammation markers and improved the lipid profile in
subjects with severe chronic periodontitis [44•].
Recommendations for Clinical Practitioners
According to the Centers for Disease Control and Prevention
(CDC), cardiovascular disease is the number one cause of
death in the USA for both men and women; about 610,000
people die from ACVD annually [49]. As for periodontal dis-
ease, it is estimated that 47.2%, or 64.7 million American
adults have mild, moderate, or severe periodontitis. In adults
age 65 and older, prevalence rate increases to 70.1% [50••].
With such a considerable population affected and/or at risk of
these two conditions, it is essential for dental professionals to
be informed of the increasing evidence suggesting periodontal
disease as a risk factor for ACVD and to refer to general
clinical guidelines when dealing with these patients [51•].
Dental professionals are recommended to do the following:
& Provide a proper periodontal diagnosis involving probing
pocket depth, checking for clinical attachment loss and for
bleeding on probing, and radiographic assessment when
treating patients with ACVD.
& Refer patients with a history of cardiovascular events to
follow the AHA guidelines for dental treatments.
& Suggest to patients who are smokers, are hypertensive, are
overweight/obese, are diabetics, or have other risks factors
for ACVD to have routine medical assessments to elimi-
nate confounding factors and to minimize their risk of
cardiovascular diseases.
& Inform patients of the strong association between peri-
odontal disease and ACVD and the plausible mechanism
of bacteremia and increased systemic inflammation.
& Provide counseling for lifestyle changes such as diet, ex-
ercise, and smoking cessation as it may have a beneficial
effect on patients’ overall health since ACVD and peri-
odontal disease both share many common risk factors.
Curr Oral Health Rep
Conclusion
The evidences clearly suggest a link between periodontal and
cardiovascular diseases even though a direct or causal link has
not been demonstrated yet. Nevertheless, it is undeniable that
both dental and medical professionals must work together to
instruct their patients on the importance of good oral health
which would help prevent further cardiovascular events such
as atherosclerosis. The guidelines provided will assist readers
in understanding the preponderant role of periodontal treat-
ments in the prevention of cardiovascular diseases. Further
longitudinal and interventional studies will help comprehend
the biological mechanism and establish a causal relationship.
Acknowledgments We would like to thank previous contributions from
Doctors C.M. Nguyen, J.W.M. Kim, V.H. Quan, and B.H. Nguyen who
led to this updated review.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does not
contain any studies with human or animal subjects performed by any of
the authors.
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