, Helene Holmer
, Michael Coleman
, Marian Tudor
, Ola Ohlsson
, G. Rutger Persson
Kristianstad Central Hospital, Kristianstad, Sweden
Aston University, Birmingham, UK
Blekinge Institute of Technology, Karlskrona, Sweden
Dublin Dental University Hospital, Trinity College, Dublin, Ireland
University of Washington, Seattle, WA, USA
School of Health and Society
Kristianstad University, SE 29188, Sweden
Phone number: + 46 44 208588
Fax number: + 46 44 209589
Short title: Periodontitis and ACS
Keywords: cardiovascular disease; serum; hs-CRP; cytokines; VEGF; oral disease; human
Number of words in abstract:
Number of words in manuscript: 2826
Number of references: 37
Conflict of Interest and Sources of Funding
None of the authors has a conflict of interest. The funding for the present study was obtained
from Kristianstad University, Sweden, from Blekinge Technical University, Sweden, and
from a research grant from the Research Council at the Central Hospital in Kristianstad,
yet to be defined. The aim of this study was to assess
if there are
differences in levels of
serum cytokines between individuals with or without ACS or periodontal comorbidity.
Material and Methods: In a case-control study, individuals with ACS (78 individuals, 10.3%
females) and matching healthy controls (78 individuals, 28.2% females) were included.
Medical and dental examinations were performed to diagnose ACS and periodontitis. Serum
levels of cytokines were assessed using Luminex technology.
and 12.8% of the individuals, respectively. The unadjusted odds-ratio that individuals with
ACS also had periodontitis was 7.5 (95% CI: 3.4, 16.8, p0.001). Independent of periodontal
conditions, individuals with ACS had significantly higher serum levels of IL8 (mean: 44.3
and 40.0 pg/ml) and
vascular endothelial growth factor (
(mean: 82.3 and 55.3 pg/ml)
cytokine expression in individuals with ACS is unrelated to periodontal conditions.
unstable angina, through to life-threatening myocardial infarctions. Limited information is
available regarding the relationships between cytokine expression in individuals with acute
coronary syndrome and periodontitis.
significantly higher serum levels of IL8 and VEGF than control individuals.
Although Practical prediction strategies for those at greatest risk of
ACS must be founded in a greater understanding of the link between circulatory and the more
easily accessible inflammatory processes, such as that which sustained periodontitisa
diagnosis of periodontitis has been associated with ACS, the inflammatory burden of
periodontitis as expressed by a panel of pro-inflammatory cytokines in serum is not possible
to identify at the time of the acute phase of coronary heart disease
This suggests that
Acute coronary syndrome (ACS), has an enormous impact on mortality and morbidity
worldwide (Timmis 2015). This term includes a range of conditions which precipitate the
occlusion of coronary arterial blood flow, such as unstable angina through to fatal myocardial
infarctions (Kaul et al. 2013). Periodontitis is a
common condition in adults
(Eke et al. 2015). (Keyes and Rams
Whilst many observational studies support a relationship between ACS and
periodontitis, causation has yet to be defined (Lockhart et al. 2012). However, individuals
with advanced periodontitis exhibit endothelial dysfunction along with evidence of systemic
inflammation, which promotes their risk of developing cardiovascular disease (Amar et al.
2003, Holtfreter et al. 2013). Whilst studies have demonstrated that periodontal treatment
improves brachial artery endothelial function (Elter et al. 2006, Seinost et al. 2005, Tonetti et
al. 2007), treatment of periodontitis did not impact the incidence of cardiovascular
complications (Offenbacher et al. 2009, Beck et al. 2008). In addition, survival statistics from
a six-year longitudinal study also failed to show that a diagnosis of periodontitis predicted
mortality in older individuals (Renvert et al. 2015). Furthermore, a systematic review of
clinical trials concluded that there was insufficient evidence to support the notion that
periodontal therapy can prevent the recurrence of cardiovascular disease in patients with
periodontitis (Li et al. 2014). There is a need to explore the systemic impact of periodontitis in
terms of inflammatory markers, which may cast light on whether periodontal inflammation
actively contributes to cardiovascular complications.
Serum high sensitivity C-reactive protein (hs-CRP) has been identified as an important
increased risk of mortality and morbidity from cardiovascular diseases (Ridker 2007).
Periodontitis is also associated with increased levels of CRP, and interleukin (IL)-18 (Buhlin
et al. 2009). Some pro-inflammatory cytokines have been studied to explore the systemic
inflammatory impact of periodontitis, leading to conflicting results. Elevated serum levels of
IL6 and tumour necrosis factor alpha (TNF-) have been demonstrated in individuals with
periodontitis in comparison with healthy individuals (Tang et al. 2011). In contrast, a report
determined TNF- levels to be significantly lower in individuals with periodontitis than
control individuals (Nakajima et al. 2010). Yet another study assessed serum TNF- levels in
individuals with or without periodontitis and failed to demonstrate a relationship between
serum TNF- levels and periodontal status (Gokul et al. 2012). Thus, the relationship between
periodontitis and system expression of TNF-α is unclear.
With regard to other potential markers which may link periodontitis with systemic conditions,
of VEGF (Savino et al. 2006). In ACS, elevated VEGF concentrations may serve as a
surrogate marker of myocardial injury (Konopka et al. 2013) and indeed, serum VEGF levels
increase with periodontitis severity (Pradeep et al. 2011). Hence, in patients at risk for ACS,
there appears to be an important interplay between various growth factors and cytokines,
which are associated with inflammatory status and platelet hyper-reactivity (Gori et al. 2009).
between oral infections and cardio-metabolic diseases it remains unclear how oral infection
may have an impact on cardiovascular diseases (Janket et al. 2015). Thus, there appears to be
no studies that have performed comprehensive analysis of serum cytokine levels in
individuals with heart disease and periodontitis in comparison to cytokine levels in
individuals without heart disease or other systemic diseases. The objectives of the present
study were to assess if there are differences in the levels of serum cytokine biomarkers
between individuals who have ACS with or without periodontal comorbidity. The null-
hypothesis is that there are no differences in serum cytokine expressions between individuals
with or without periodontitis and/or ACS pathology.
Material and Methods
In compliance with the Declaration of Helsinki, the Regional Ethics Committee in Lund,
Sweden, approved the study (Institutional Review Board approval no. LU556-00). After the
details of the original study protocol had been presented (Persson et al. 2003, Renvert et al.
2010, Renvert et al. 2006) informed consent was obtained from the individuals. Briefly,
consecutively surviving individuals admitted to the Kristianstad Central Hospital were
enrolled if they had a diagnosis of ACS defined by chest pain associated with typical
electrocardiogram (ECG) changes. The initial ECG was considered diagnostic for myocardial
infarction if there was ST segment elevation of 2 mm or more in a chest lead, or ST segment
elevation of 1 mm or more in a limb lead. ST depression and/or T-wave inversion changes
combined with typical serial pattern of cardiac markers [i.e. creatinine kinase isoenzyme
(CKMB) and troponin T (TnT)] according to local laboratory standards, were also considered
diagnostic for myocardial infarction. Left bundle block (LBB) was considered diagnostic for
myocardial infarction if chest pain combined with typical serial pattern of cardiac markers
were present. At the time of admission, a blood sample was taken for further analysis of
biomarkers of inflammation.
Approximately one month after treatment and release from hospital
individuals with a diagnosis of ACS received a comprehensive periodontal examination. The
periodontal examination included routine measurements of probing pocket depths, extent of
gingival inflammation and radiographic analysis of alveolar bone loss. The methods used to
diagnose gingivitis and bone loss have been described in detail (Persson et al. 2003). In the
present study, individuals with loss of alveolar bone, verified by a distance between cement
enamel junction and the highest coronal bone level exceeding 4 mm, at ≥30 % of teeth,
combined with bleeding on probing (BOP) ≥20 % and a probing pocket depth ≥5 mm at four
teeth or more were considered as having periodontitis.
All study individuals were examined
by one and the same examiner (Susanna Persson-Sättlin, dental hygienist)
(Renvert et al.
medical data. Study individuals were instructed not to provide any pertinent information in
regards to cardiovascular events
diagnosis of ACS, or a diagnosis of ACS within 3 years after the enrolment in the present
study, were included (Persson et al. 2003, Renvert et al. 2010). The control individuals were
identified among friends to those with a current ACS or from registry available to the
Data based on analysis of 80 patients with ACS and 80 control individuals from
a group consisting of friends of the patients (39 individuals) with ACS, and from a research
registry of subjects (41 individuals) who had participated in a timely health survey (Back et
al. 1999). The 41 individuals identified from the health survey were selected based on a best
fit principle (age, gender, smoking status, socio-economics) in comparison to the individuals
in the test group.
The control individuals also received a comprehensive cardiological medical examination at
Following the medical examination, the control individuals also received a comprehensive
dental examination consistent with the examinations that the individuals with ACS received.
The present study design complies with the STROBE initiative
A broad panel including 23 pro- and anti-inflammatory cytokines was assessed using
Luminex MagPix multi analyte technology (Luminex, Austin TX. USA).
This panel included
the following cytokines; Basic FGF , Eotaxin, GCSF (granulocyte colony-stimulating factor),
IFN interferon gamma), Interleukin (IL): IL1β (interleukin 1 beta), IL1ra (receptor
antagonist), IL4, IL5, IL6, IL7, IL8,
IP10 (interferon-inducible protein-10), MCP1 (monocyte chemo-attractant protein-1), MIP1a
(macrophage inflammatory protein 1alpha ), MIP1b (macrophage inflammatory protein
1beta), PDGFBB (platelet-derived growth factor subunit B), TNFα (tumor necrosis factor
alpha), and VEGF (Vascular endothelial growth factor).
The cytokine kit was purchased from
Bio-Rad (Sundbyberg, Sweden) and the cytokines were detected following the manufacturer’s
instructions. The researcher who performed the cytokine analysis was unaware of where the
samples represented individuals with periodontitis or not, or any other clinical data. Briefly,
samples were defrosted, incubated with antibodies, immobilized on color-coded magnetic
beads, washed to remove unbound material, and then incubated with biotinylated antibodies.
After further washing, a streptavidin-phycoerythrin conjugate, which binds to the biotinylated
antibodies, was added before a final washing step. The Luminex analyser determined the
magnitude of the phycoerythrin-derived signal. Duplicate readings were performed in a subset
of samples demonstrating a high level of agreement between measurements with intra-class
Formatted: Font: Italic
correlation (ICC) varied between 0.95 and 1.0 (p<0.001).
Serum for the analysis of cytokines
were not available for all individuals, Therefore, 76 individuals in the test and control groups
were included, respectively.
The statistical package SPSS 22 for Windows was used for all analyses. Multivariate analysis
with Bonferroni correction adjusted for gender was used to determine whether significant
differences in cytokine levels existed between study groups. Chi-square analysis was used for
dichotomized data. Independent t-tests (equal variance not assumed) were used for numerical
aenszel common odds ratio was calculated. Due to the absence of
periodontitis were not available at the time of study design a sample size calculation was not
possible to perform prior to the study. In previous reports on this study materiel in regards to
gender, smoking status, and age we have failed to identify that these factors were confounders
(Persson et al. 2003, Renvert et al. 2004).
Data from 156 adult individuals including 76 individuals with a diagnosis of ACS (10.3 %
females), and from 76 control individuals without clinical evidence of cardiovascular disease
were included (28.2 % females). The mean age of individuals in the ACS and control groups
was 59.7 years (S.D. 9.2) and 59.7 years (S.D. 9.1), respectively. Serum lipid values, white
blood cell counts, HbA1c levels were within the reference range for normal conditions.
Characteristic medical values are presented in Table 1.
In the ACS group as well as in the control group statistical analysis failed to demonstrate that
difference in the frequency of ACS by age (p=0.96), smoking (p=0.60) or number of
remaining teeth (p=0.29). In the ACS and control groups 22.7 % and 19.2 % were smokers,
respectively. A diagnosis of periodontitis in the ACS and control group was diagnosed in 52.6
% and 12.8 % of the individuals, respectively. The unadjusted
odds-ratio that individuals with ACS also had periodontitis was 7.5 (95 CI: 3.4, 16.8,
p0.001). The prevalence of gingivitis (
bleeding on probing
4 per tooth
not differ by cardiovascular status. In fact, 100 % of the individuals with ACS and 97.3 % of
the control individuals presented with gingivitis. Evidence of alveolar bone loss (≥4 mm at
≥30 % of teeth) was 73.1 % in the ACS group and 23.1 % in the control group (p<0.001).
In the control group (individuals without a diagnosis of ACS) statistical analysis failed to
diagnosis of periodontitis. In individuals with a diagnosis of ACS statistical analysis also did
not demonstrate differences in hs-CRP levels (p=0.41) between those with or without a
diagnosis of periodontitis. Serum hs-CRP values were significantly higher in individuals with
a diagnosis of ACS in comparison to those individuals without a diagnosis of ACS (p<0.001).
Multivariate analysis adjusting for gender failed to demonstrate differences in serum cytokine
levels in both ACS and control groups.
Mean values and standard deviations for 23 cytokines studied in individuals with or without
ACS are presented. Independent of periodontal conditions, individuals with ACS had
significantly higher serum levels of IL8 (mean value: 44.3 and 40.0, respectively, mean diff:
diff: 1.6, 95 % CI: 1.2, 7.5, p<0.01)
and VEGF (mean value: 82.3 and 55.3,
respectively, mean diff: 27.0, SE.
diff: 9.4, 95 % CI: 8.4, 45.4, p<0.01) than control
periodontitis or not made no difference in serum cytokine expression. Individuals with ACS
without periodontitis had higher serum levels of VEGF than control individuals without
periodontitis (mean value: 90.0 and 55.1, respectively, mean diff: 34.9, SE.
diff: 12.8, 95 %
cardiovascular health to
both periodontitis and ACS serum VEGF levels increased
The present study identified a high odds ratio that individuals with ACS also had
periodontitis. This finding is consistent with several other studies. The present study also
demonstrated that a subset of pro-inflammatory cytokines were found at high levels in
individuals without a diagnosis of periodontitis but with ACS. This suggests that periodontitis
may not to any greater extent contribute to the inflammatory burden of a person at risk for or
having ACS. The impact of the current ACS status may overshadow the inflammatory impact
of periodontitis. A recent meta-analysis has demonstrated scientific evidence that periodontal
therapies may improve improve endothelial function and reduce biomarkers (i.e. hs-CRP,
TNF- and IL6) of atherosclerotic disease, especially in those already suffering from heart
disease and/or diabetes (Teeuw et al. 2014).
The present study failed to demonstrate that a diagnosis of periodontitis enhanced the
expression of serum cytokine levels in individuals with ACS. We did show that elevated
levels of IL8 and VEGF were associated with a diagnosis of ACS. Consistent with other
studies, however, serum hs-CRP levels were significantly higher in individuals with ACS and
periodontitis than in healthy control individuals (no clinical evidence of ACS or
periodontitis). Gingival bleeding and probing pocket depth did not impact serum hs-CRP or
serum cytokine levels. Consistently, the present study also failed to demonstrate a difference
in serum hs-CRP levels in individuals with or without periodontitis and in the absence of a
diagnosis of ACS. This is in broad agreement with the current literature in this area (Baser et
al. 2014, Renvert et al. 2013). The identified lack of impact on serum cytokine levels when
gingival bleeding was included may be explained by the high prevalence of gingival
inflammation in all study individuals. The decision to use serum samples to assess the
presence of pro and anti-inflammatory cytokines was based on the concept that systemic
hyper-inflammation may, in part be related to the pathology of periodontitis. To the best of
our knowledge there are limited data on the impact of periodontitis on the levels of a broader
panel of cytokines in serum from individuals with or without ACS.
VEGF is a cytokine that is known to be involved in angiogenesis. It has been shown that
activity in the ischemic-necrotic myocardium (Lee et al. 2004). Levels of VEGF in serum
correlate with clinical parameters of periodontal disease and serum VEGF levels increase
progressively with the severity of periodontitis (Pradeep et al. 2011), contributing to its
pathogenesis (Artese et al. 2010, Prapulla et al. 2007). Our findings are consistent with these
observations. Studies of gingival biopsies at different stages of inflammation have shown that
levels of VEGF are related to endothelial proliferation in gingival tissues collected from
individuals with chronic periodontitis (Kasprzak et al. 2012). Elevated VEGF levels in
individuals with chronic periodontitis are linked with VEGF and β-defensin-1 gene
polymorphisms (Tian et al. 2013). The present study identified that serum concentrations of
VEGF were associated with ACS but not to periodontitis. Data have shown that in ACS
serum VEGF concentrations are elevated and can serve as a surrogate marker of myocardial
injury (Konopka et al. 2013). Data have also suggested that VEGF induces IP10 expression,
which is a pro-inflammatory marker which is associated with the developing and chronic
pathology of ACS process (Boulday et al. 2006, Frangogiannis 2004, Wilsgaard et al. 2015).
Chronic periodontitis presents with phases of disease activity and quiescence. Although the
established, such criteria cannot identify active periodontitis. Most likely, analysis of serum or
gingival crevicular fluid levels of pro- and anti-inflammatory cytokines may distinguish
between chronic and acute periodontitis. There is a need to further explore serum cytokine
threshold levels that indicate periodontal inflammation. It is possible that additional studies of
the infectious bacterial aetiology in periodontitis in relation to clinical and cytokine data can
cast light on periodontal disease activity and its impact on cardiovascular disease. Whilst the
present report revealed that elevated cytokine levels were associated with periodontitis and
coronary disease, it is recognised that there are practical limitations on the interpretation of
the expression of pro- and anti-inflammatory cytokines, in terms of time- and event
dependency, which make their clinical predictivities potentially problematic.
One limitation of the present study is that the subgroup analyses included relatively few cases.
The present study is based on a cohort of individuals who either were admitted to emergency
care with a diagnosis of ACS, or who belonged to a sample of the community without a
confirmed diagnosis of heart disease. Nevertheless, the study design represents case selection
based on consecutive cases with ACS and is therefore not likely to be influenced by
periodontal status. In addition, the individuals that had received treatment for ACS had most
likely been prescribed medications which could have impacted periodontal status during the
time of dental examination. Logistically, it was not possible to perform the dental
examination at the time of admittance to the hospital for ACS. The investigators have no
information about past diagnosis and treatment of periodontitis, on the progression of
periodontitis, or if these study individuals with or without periodontitis were in a current or
recent phase of active periodontitis or not and that could have had an impact on pro-
inflammatory cytokine levels.
Information on Body Mass Index (BMI) was not collected.
Therefore, no adjustment for this factor could be made. Data analysis on the impact of age,
gender, and smoking status in previous reports (Persson et al. 2003, Renvert et al. 2004) have
failed to identify that these factors were confounders to the outcome. The explanations to this
can be explained by the study design to match individuals in test and control groups, and to
the fact that few individuals were smokers, and that the the age range was narrow.
In spite of the fact that few individuals were smokers, all individuals had poor oral hygiene
diagnosis, including data on gingival inflammation, pocket depths, and bone loss was
predominantly defined by data based on alveolar bone loss evaluations. The analysis of serum
from the individuals with ACS was performed on blood samples collected at the time of
admission and before any medical intervention or medication. Thus, the cytokine levels in
serum represent a ‘snapshot’ of cytokine expression at that particular time point of admission.
Likewise, the blood samples from the control individuals were collected from individuals who
were not taking medication or had had their medication changed within the preceding three
In conclusion, a diagnosis of ACS had a major impact on serum cytokine expression and
cytokine expression in individuals with ACS to be unrelated to periodontal conditions.
We appreciate the work by Ms. Susanna Sättlin, dental hygienist at Dental Public Health
Services Specialty Clinic of Periodontology, Kristianstad, Sweden for the clinical periodontal
examinations of all study individuals
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Figure 1. Box-plot diagram illustrating differences in hs-CRP levels by cardiovascular and
periodontal status ( = outlier).
Figure 2. Box-plot diagram illustrating differences in VEGF levels by cardiovascular and
Table 1. Mean levels and standard deviations of medical values in control and ACS
High density lipids (mmol/l)
Low density lipids (mmol/l)
Table 2. Mean levels and standard deviations of serum cytokines in control individuals and
individuals with a diagnosis of ACS. (* = significant differences between groups, p<0.01)
Table 3. Levels of cytokines in serum from control individuals without periodontitis (n=68) or
with periodontitis (n=10) and individuals with a diagnosis of ACS without periodontitis
(n=37) or with periodontitis (n=41). Data are presented for mean values, mean differences,
S.E. mean diff, 95 % CI and significance when adjusted for smoking history.
95 % CI
Data analysis failed to show differences by periodontal status in individuals with