ArticlePDF AvailableLiterature Review

Abstract

Objective: The primary objective was to investigate the relationship between periodontitis and hypertension in two independent large surveys. The secondary objective was to ascertain whether systemic inflammation had a mediation effect in the association. Methods: This cross-sectional study analyzed representative samples of the US (n=3460; NHANES 2009/10) and Korean (n=4539; 2015 KNHANES VI-3) populations. The association between periodontitis (exposure), hypertension (outcome) and inflammatory markers [C-reactive protein (CRP) and white blood cell counts (WBC)] (mediators) was assessed using multivariate linear and logistic regression models and mediation analysis. Results: Participants with periodontitis were more likely to have hypertension (NHANES:OR=1.3, 95%CI:1.0-1.6, p=0.025; KNHANES:OR=1.2, 95%CI:1.0-1.4, p=0.041) and actual systolic blood pressure ≥140 mm Hg (NHANES:OR=1.6, 95%CI:1.1-2.3, p<0.001; KNHANES:OR=1.3, 95%CI:1.0-1.6, p<0.031) than those without the disease. These associations were independent of age, gender, BMI, education level, smoking, alcohol consumption, creatinine, physical activity, presence of other comorbidities and confirmed in participants not taking antihypertensive medications. Diagnosis of periodontitis was directly associated with WBC (in both surveys- NHANES:β±SE=0.3±0.1, p<0.004; KNHANES:β±SE=0.3±0.1, p<0.001) and with CRP levels (in one survey: NHANES:β±SE=0.1±0.03, p<0.007; KNHANES:β±SE=0.1±0.04,p>0.213). Mediation analyses confirmed that CRP acted as a mediator in the association between periodontitis and hypertension in both populations (Mediated effect: NHANES:β±SE=0.010±0.003, p<0.001; KNHANES:β±SE=0.003±0.001, p=0.015). WBC acted as a mediator in the KNHANES (Mediated effect:β±SE=0.004±0.001, p=0.004) whilst in the NHANES its effect was dependent of CRP inclusion in the model (Mediated effect WBC+CRP:β±SE=0.002±0.001, p=0.001). Conclusions: These findings suggest that periodontitis is closely linked to hypertension and systemic inflammation is, in part, a mediator of this association.
Accepted Article
This article has been accepted for publication and undergone full peer review but
has not been through the copyediting, typesetting, pagination and proofreading
process, which may lead to differences between this version and the Version of
Record. Please cite this article as doi: 10.1111/JOIM.13180
This article is protected by copyright. All rights reserved
DR. EVA MARIA MUÑOZ AGUILERA (Orcid ID : 0000-0002-2225-5624)
Article type : Review
Corresponding author mail id: f.daiuto@ucl.ac.uk
Is Systemic Inflammation a Missing Link Between Periodontitis and
Hypertension? Results from Two Large Populations-based Surveys.
Running headline: Periodontitis, hypertension and systemic inflammation.
Authors: Eva Muñoz Aguilera, BDS, MClinDent*1,2, Yago Leira, BDS, PhD*1,3, Queralt Miró
Catalina,BS, MS4, Marco Orlandi, BDS, PhD1, Marta Czesnikiewicz-Guzik, BDS, PhD5,6, Tomasz J.
Guzik, MD, PhD7,8, Aaron D. Hingorani, MD, PhD9, José Nart, BDS, PhD2, Francesco D’Aiuto, DMD,
PhD§1
*Equally first author
§Corresponding author
Affiliations:
1Periodontology Unit, UCL Eastman Dental Institute and Hospital, University College London, London,
UK.
2Department of Periodontology, Universitat Internacional de Catalunya, Barcelona, Spain.
3Periodontology Unit, Faculty of Odontology, University of Santiago de Compostela & Medical-
Surgical Dentistry (OMEQUI) Research Group, Health Research Institute of Santiago de Compostela
(IDIS), Santiago de Compostela, Spain.
4Department of Statistics, Universitat Internacional de Catalunya, Barcelona, Spain
5Department of Periodontology and Oral Sciences Research Group, University of Glasgow Dental
School, Glasgow, UK.
6Department of Experimental Dentistry and Dental Prophylaxis, Jagiellonian University, Krakow,
Poland.
7Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK.
8Department of Internal and Agricultural Medicine, Jagiellonian University, Krakow, Poland.
9Genetic Epidemiology, Institute of Cardiovascular Science, Faculty of Population Health Sciences,
University College London, London, UK.
Accepted Article
This article is protected by copyright. All rights reserved
Abstract:
Objective: The primary objective was to investigate the relationship between periodontitis and
hypertension in two independent large surveys. The secondary objective was to ascertain whether
systemic inflammation had a mediation effect in the association.
Methods: This cross-sectional study analyzed representative samples of the US (n=3460; NHANES
2009/10) and Korean (n=4539; 2015 KNHANES VI-3) populations. The association between
periodontitis (exposure), hypertension (outcome) and inflammatory markers [C-reactive protein (CRP)
and white blood cell counts (WBC)] (mediators) was assessed using multivariate linear and logistic
regression models and mediation analysis.
Results: Participants with periodontitis were more likely to have hypertension (NHANES:OR=1.3,
95%CI:1.0-1.6, p=0.025; KNHANES:OR=1.2, 95%CI:1.0-1.4, p=0.041) and actual systolic blood
pressure ≥140 mm Hg (NHANES:OR=1.6, 95%CI:1.1-2.3, p<0.001; KNHANES:OR=1.3, 95%CI:1.0-
1.6, p<0.031) than those without the disease. These associations were independent of age, gender,
BMI, education level, smoking, alcohol consumption, creatinine, physical activity, presence of other
comorbidities and confirmed in participants not taking antihypertensive medications. Diagnosis of
periodontitis was directly associated with WBC (in both surveys- NHANES:β±SE=0.3±0.1, p<0.004;
KNHANES:β±SE=0.3±0.1, p<0.001) and with CRP levels (in one survey: NHANES:β±SE=0.1±0.03,
p<0.007; KNHANES:β±SE=0.1±0.04,p>0.213). Mediation analyses confirmed that CRP acted as a
mediator in the association between periodontitis and hypertension in both populations (Mediated
effect: NHANES:β±SE=0.010±0.003, p<0.001; KNHANES:β±SE=0.003±0.001, p=0.015). WBC acted
as a mediator in the KNHANES (Mediated effect:β±SE=0.004±0.001, p=0.004) whilst in the NHANES
its effect was dependent of CRP inclusion in the model (Mediated effect
WBC+CRP:β±SE=0.002±0.001, p=0.001).
Conclusions: These findings suggest that periodontitis is closely linked to hypertension and systemic
inflammation is, in part, a mediator of this association.
Key words: Periodontitis, Hypertension, High blood pressure, Systemic inflammation, CRP,
Leukocytes
Accepted Article
This article is protected by copyright. All rights reserved
Introduction
Hypertension is a complex multifactorial disorder. Its prevalence exceeds 31% worldwide with more
than 1.13 billion people affected (1). Elevated blood pressure (BP) is strongly linked to cardiovascular
complications, increasing morbidity and mortality (2). Experimental and observational evidence
supports a prominent role of systemic inflammation both in the initiation and progression of
hypertension (3). The management of this condition, however, is still a challenge and it represents an
increasing burden for society.
Periodontitis is one of the most common inflammatory disorders worldwide with >46% of adults in the
US diagnosed with the disease (4). Strong evidence supports the role of a dysbiotic dental biofilm in
the development of periodontitis. Further a cluster of modifiable risk factors are shared between
periodontitis and leading non communicable diseases (NCDs) (cardiovascular diseases, cancer,
chronic respiratory diseases and diabetes) (5).
Patients with periodontitis exhibit not only gingival inflammation but also endothelial dysfunction,
increased bacterial burden (endotoxins and exotoxins dissemination), metabolic dysregulation, and
systemic inflammation (6-9). A bi-directional link has been proposed between periodontitis and other
metabolic disorders such as metabolic syndrome and diabetes (10, 11).
Hypertension has been linked to periodontitis but evidence from intervention trials is limited (12). A
possible causal relationship between these two conditions has been proposed recently using
Mendelian Randomization. This analysis confirmed a link between genetic variants linked to
periodontitis and elevated BP phenotypes in a large UK population study (13). The exact mechanisms
mediating this association remain unknown raising the question of whether inflammation or bacterial
burden could play a prominent role. Given that systemic inflammatory biomarkers such as C-reactive
protein (CRP) and leukocyte counts have been correlated with both periodontitis and hypertension,
we hypothesized that systemic inflammation could be a mediator between the two diseases.
Therefore, confirmation of this association in large independent studies with a focus on mediators
need to be unraveled prior to undertaking interventional trials investigating the treatment of
periodontitis as a target non-pharmacological treatment for hypertension. Accordingly, the primary aim
of this study was to investigate the association between periodontitis and hypertension using two
representative surveys of the US and Korean populations. The secondary aim was to ascertain the
role of systemic inflammation in mediating this association.
Accepted Article
This article is protected by copyright. All rights reserved
Material and methods:
Two population-based surveys were analyzed and hereby reported in compliance with the
Strengthening the Reporting of Observational studies in Epidemiology (STROBE) guidelines
(Supplemental checklist).
Survey designs and study populations
Databases obtained from the US [2009/2010 National Health And Nutrition Examination Survey
(NHANES)] and Korean [2015 VI-3 Korean National Health And Nutrition Examination Survey
(KNHANES)] open repositories shared similar study design (stratified, multistage cluster probability
sampling survey) (14, 15) and they were conducted by the statistical division of the National Centers
for Disease Control and Prevention in US and Korea respectively. The study was conducted in
accordance with the 1975 Declaration of Helsinki and participants provided written consent. These
survey waves were selected for this study as were the first ones containing a detailed periodontal
examination, measurements of average BP, serum concentrations of high sensitivity CRP (hs-CRP),
and white blood cell counts (WBC).
Exclusion criteria used in the final sample analysis were (i) age <30 years in the NHANES (N=6,451)
as no periodontal data was collected and age <19 years in the KNHANES (N=1,345); (ii) pregnancy
(NHANES, N=23; KNHANES, N=29); (iii) lack of data on hs-CRP (NHANES, N=137; KNHANES,
N=243); (iv) lack of data on BP (NHANES, N=123; KNHANES, N=29) and (v) lack of periodontal data
for any other reasons (NHANES, N=343, KNHANES, N=792). From a total of 10,537 participants in
the NHANES 2009/2010 and 6,977 in the KNHANES VI-3, the final samples included in this analysis
were of 3,460 and 4,539 participants respectively. These populations refer to a representative sample
of just over 128 millions of US and 33 millions of Korean citizens.
We extracted data on sociodemographic, health lifestyle behavioral factors, anthropometric
measurements, medical history, oral examination, mean BP and biochemical parameters (eTable 1).
Blood pressure measurements
In both cross-sectional studies, sitting BP was measured using a standardized protocol (16). Average
measurements of systolic and diastolic arterial pressure (SBP and DBP) were obtained from three
consecutive readings. Participants were then categorized as normal, prehypertensive, and
hypertensive according to the Joint National Committee 7 guidelines (17). Further, hypertension was
Accepted Article
This article is protected by copyright. All rights reserved
defined as values of SBP ≥140 mmHg or DBP ≥90 mmHg or the use of antihypertensive medication
(18). The number of participants taking antihypertensive medications was also calculated.
Periodontal examination and dental exposure variables
The analysis was conducted using both established case definitions as well as continuous measures
(full mouth indices) of periodontitis. However, different protocols were used. In the NHANES, a full-
mouth periodontal assessment was carried out at six sites per tooth and periodontitis (exposure) was
defined as mild, moderate or severe (19). Continuous aggregate dental variables (number and
percentage of sites) were then created to indicate a) the extent of periodontal lesions with probing
pocket depths (PPD) of ≥ 4mm, ≥5mm, ≥6 mm and b) the extent of loss of periodontal tissue
attachment (AL) of ≥3mm, ≥ 4 mm, ≥5mm, ≥6mm as previously described (20).
In the KNHANES study, participants presenting with CPI scores of 3 and 4 (at least in one sextant)
were defined as having worse periodontal status, whereas those presenting scores of 0, 1 and 2
represented controls with better periodontal status. Continuous measures of periodontal lesions were
then created as follows: a) CPI cumulative score (the sum of only CPI scores of 3 or 4 of all sextants);
and b) CPI continuous score (sum of all CPI scores of all sextants) as previously described (21).
Laboratory analysis
Biochemical parameters were retrieved from both surveys including plasma glucose (mg/dL), insulin
levels (uIU/mL), glycated hemoglobin [HbA1c (%)], total cholesterol (mg/dL), high- and low-density
lipoprotein cholesterol levels [HDL and LDL (mg/dL)], triglyceride levels (mg/dL), creatinine (mg/dL),
hs-CRP (mg/dL), and WBCs (thous/μL)].
Statistical analysis
Data analyses were performed with STATA version 15.0 (StataCorp, College Station, Tex, US) and R
Software (version 3.5.2). Continuous variables are reported as mean ± standard error (SE), whereas
categorical variables are expressed as percentages. Simple differences between participants with or
without periodontitis were assessed by independent t-test (for continuous variables) or χ square test
(for categorical variables). Normality assumptions were checked, and a logarithmic transformation of
hs-CRP was used for parametric analyses. Different measures of oral disease exposure (categorical
and continuous) were adopted to test the association between periodontal status and BP. Further,
circulating levels of WBC and hs-CRP were used as biomarkers of systemic inflammation and
possible mediators of the association between periodontal status and hypertension. Univariate
Accepted Article
This article is protected by copyright. All rights reserved
analyses were performed for all continuous variables comparing the groups of participants with
periodontitis/worse periodontal status and the rest of the study sample. All those variables with
statistically significant associations were then used in the multivariate models.
Multivariate logistic regression models were created to test potential associations between
periodontitis case definitions or continuous measures of periodontal lesions with hypertension, SBP
≥140 mmHg or hs-CRP>2mg/L as outcome variables. Multivariate linear regression models were then
constructed to investigate the association between periodontal (both categorical and continuous) and
arterial BP (mean SBP/DBP) variables. Similar analyses were performed with hs-CRP and WBC
values (exposures) and hypertension (as categorical or continuous outcomes). Odds ratios (ORs) and
95% confidence intervals (CI) were calculated as well as β coefficient with standard errors. A fully
adjusted model (Model 1) included age, gender, ethnicity, smoking, education level, and chronic
medical conditions as covariates (as previously reported) in both surveys (18). In addition to these,
body mass index (BMI), alcohol consumption, creatinine and physical activity were included in the
multivariable models of the KNHANES survey (as they all presented univariate association with the
outcome variables).
Sensitivity analyses in the subgroup of participants not taking antihypertensive medications were also
performed (Model 2) (NHANES, N=2486; KNHANES, N=3270).
Structural equation modelling (SEM) was then used to estimate whether the association between
periodontitis and hypertension was mediated by WBC or CRP using R Software (22). Four different
and prespecified routes were used, direct (route 1) and indirect (route 2, 3, 4) mediation effects with
their 95% CI were estimated:
Route 1: Periodontitis (exposure) → Hypertension (outcome).
Route 2: Periodontitis (exposure) → WBC (mediator) → Hypertension (outcome).
Route 3: Periodontitis (exposure) → Log CRP (mediator) → Hypertension (outcome).
Route 4: Periodontitis (exposure) → WBC (mediator) → Log CRP (mediator) → Hypertension
(outcome).
Accepted Article
This article is protected by copyright. All rights reserved
Results
Characteristics of study populations
Participants with periodontitis were predominantly men (NHANES, 60%; KNHANES, 57%), older than
50 years of age, increased number of current smokers (NHANES, 52% vs 36%; KNHANES, 23% vs
15%), of lower education background and higher prevalence of diabetes (NHANES, 12% vs 6%;
KNHANES, 10% vs 5%) than participants without periodontitis (Table 1). Almost a doubled
prevalence of hypertension (NHANES, 42% vs 25%; KNHANES, 39% vs 19%) and anti-hypertensive
medication (NHANES, 31% vs 19%; KNHANES, 25% vs 12%) were observed in patients with
periodontitis. Similarly, participants with periodontitis had higher values of SBP (6.4 mm Hg higher in
NHANES and 7.3 mm Hg higher in KNHANES) than survey participants without periodontitis. In the
NHANES survey, Mexican and non-Hispanic black presented with the greatest prevalence of
periodontitis. Lastly, when other traditional cardiovascular risk factors were assessed, patients with
periodontitis exhibited greater values of glucose, triglycerides, hs-CRP and WBC in both surveys
when compared to those without periodontitis, with BMI being higher in periodontitis patients only in
KNHANES (all p<0.001).
Logistic Regression Analyses
Multiple logistic regression models confirmed that among participants with periodontitis and worse
periodontal status, the adjusted odds of hypertension were 1.3 (95%CI 1.0-1.6) in the NHANES and
1.2 (95%CI 1.0-1.4) in the KNHANES populations, respectively (Table 2). Greater odds of
hypertension in patients with periodontitis and worse periodontal status (CPI 3-4) were observed in
the subgroup of participants not taking anti-hypertensive medications (NHANES: OR=1.4, 95%CI 1.0-
1.8, N=2486; KNHANES: OR=1.3, 95%CI 0.9-1.7, N=3270). Similar associations were found between
diagnosis of periodontitis and worse periodontal status (CPI 3-4) and SBP≥140 values in both
populations (NHANES: OR=1.6, 95%CI 1.2-2.1; KNHANES: OR=1.3, 95%CI 1.0-1.6) with greater
odds in participants with more severe periodontitis. These findings were consistent in those
participants not taking anti-hypertensive medications (Model 2) although the estimates were smaller
than those observed in the whole sample (Table 2). Indeed, NHANES participants with severe
periodontitis also presented with more than twice increased likelihood of SBP≥140 mm Hg in model 1
(OR=2.5 95%CI 1.7-3.6) and model 2 (OR=2.3 95%CI 1.4-3.6), respectively (Table 2).
Accepted Article
This article is protected by copyright. All rights reserved
When hs-CRP or WBC were introduced as independent exposure variables, the odds of hypertension
and SBP≥140 mm Hg ranged from 1.0 to 1.4 in the US and from 1.0 to 1.1 in the Korean survey. Only
some continuous measurements of periodontitis (mean PPD and mean CAL) were associated with
greater odds of hypertension, SBP≥140 mm Hg, and of hs-CRP2 mg/l in the fully adjusted model
and in those participants not taking antihypertensive medications (Figure 1).
Linear Regression Analyses
Linear regression analyses confirmed that periodontitis (assessed both as categorical and continuous
variables) was associated with mean SBP. These findings were confirmed in the subgroup of
participants not taking antihypertensive medications in the US survey (Table 3). In the Korean survey,
the cumulative CPI score was consistently associated with SBP and DBP and this was also confirmed
in participants not taking BP medications. Higher WBC counts were associated with mean SBP in
both surveys, whilst higher hs-CRP levels were associated with SBP and DBP only in the US study
(Table 3). Further, we observed a negative association between DBP and the number or percentage
of gingival sites with attachment loss of ≥ 3 mm and of sites with probing depth 6 mm in the
NHANES (model 2) and with the cumulative CPI score in the KNANES (models 1 and 2) (Table 3).
Lastly, both US and Korean participants with severe periodontitis or worse periodontal status (CPI 3-
4) exhibited greater systemic inflammation as assessed by hs-CRP serum levels and by WBC when
compared to those without periodontitis or better periodontal status (CPI 0-2) and this difference was
independent of other common confounders (Table 4).
Mediation Analyses
The association between periodontitis and hypertension (categorical) was mediated by CRP
(β±SE=0.010±0.003; p<0.001) in the NHANES dataset, whilst WBC (β ±SE=0.001±0.001; p=0.221)
was only an indirect mediator of the association (indirect route linked to hs-CRP) (Model A,
unadjusted) (Figure 2 A and eTable 2). When repeating the same analysis in the KNHANES
database, both hs-CRP (β±SE=0.003±0.001; p=0.015) and WBC (β±SE=0.004±0.001; p=0.004)
acted as mediators of the association between worse periodontal status and hypertension (Figure 2 B
and eTable 2). Models B, D, C replicated these results when the analyses applied for continuous
periodontal (PPD, CAL in NHANES, and CPI continuous in KNANES) and BP (SBP) variables, in both
adjusted and unadjusted models (eTable 2).
Accepted Article
This article is protected by copyright. All rights reserved
Discussion:
The analysis of two of the largest population-surveys with available dental and general health data
demonstrated that both categorical and continuous measures of periodontitis were consistently
associated with hypertension and SBP independent of other common cardiovascular risk factors.
Participants in the US with severe periodontitis had higher odds for SBP≥140 mm Hg when compared
to participants without periodontitis and all findings were confirmed in participants not taking anti-
hypertensive medications. Systemic inflammation defined by two commonly measured biomarkers
(hs-CRP and WBC) was not only associated independently with periodontitis, SBP and diagnosis of
hypertension but acted as a modest mediator of these associations.
This analysis confirmed that participants with periodontitis have a 20-60% greater chance of
presenting also a concomitant diagnosis of hypertension and a 10% to 2.5 times greater chance of
SBP≥140 mm Hg. This is consistent with previous studies reporting that patients with periodontitis
have on average 4.5 higher mean SBP (95% CI: 2.886.11) than participants without periodontitis
(12). In the present study, a higher mean SBP of 6.4 mm Hg (NHANES, 95%CI 5.3-7.4) and of 7.2
mm Hg (KNHANES, 95%CI 6.1-8.4) were observed when participants with periodontitis were
compared to those without the disease. The magnitude of this association could have important public
health implications if we consider that high sodium intake with the diet is linked to a 6.0mmHg higher
average SBP (23). Further SBP is a strong independent risk predictor for coronary heart disease
events, stroke, heart failure and end-stage renal disease (24, 25).
Negligible associations of measures of periodontitis with DBP have been reported (20, 26).
Interestingly, we observed a negative linear association between two measures of continuous disease
and DBP in both datasets. This observation has not been reported previously, and it seems to be in
contrast with the findings related to SBP. At this stage it is speculative to suggest a biological
explanation of these findings. Authors consider important the role of residual confounding from other
traditional risk factors variables (i.e. age, gender, ethnicity) as the estimates of association between
DBP and some of the continuous measures of periodontitis tended to be greater in multivariate fully
adjusted models. DBP is not considered on its own as a strong predictor for CVD events (27, 28), and
the role of inflammation on affecting this measure of blood pressure is unclear. Further research
should be conducted to ascertain the degree of association between diastolic pressure and
periodontal inflammation as well as investigate potential biological mechanisms linking them.
Accepted Article
This article is protected by copyright. All rights reserved
When comparing the findings between the two surveys, a stronger association of categorical and
continuous variables of periodontitis and gingival inflammation with hypertension and SBP were
observed in the US dataset when compared with the Korean data survey. Similar findings were found
for the association between biomarkers of inflammation (CRP and leucocytes counts) with measures
of arterial blood pressure. Whilst the two sample populations present ethnic and socio-economic
differences including a higher proportion of current smokers, adiposity and chronic medical conditions
in the US population, authors believe that the different clinical measures of periodontitis recorded in
the surveys could influence the results of the analyses.
A recent intervention study assessing the impact of periodontitis treatment on arterial blood pressure
confirmed a substantial reduction of SBP after 2 months (mean difference of 11.1 mmHg) (13). This
preliminary evidence suggests that periodontal treatment could represent a novel non-
pharmacological intervention for hypertension of similar magnitude of other lifestyles adjustments
(weight loss, increasing physical activity, salt or alcohol intake reduction or smoking cessation) with
an average reduction of SBP ranging from 4.6 to 6.4 mmHg (29-31). However, larger and longer
RCTs are needed.
Several lines of evidence now implicate inflammation in the development and progression of vascular
diseases. For the last 3 decades inflammation has been recognized as a common denominator of
early vascular dysfunction, leading onto the development of atheroma and vascular complications
(32). Recent proof of concept evidence suggests that targeting upstream inflammation by selective
drugs results in reduced morbidity and mortality (33). This could also be applicable in hypertension.
Experimental and human studies have documented several pathways by which elevated inflammatory
markers such as CRP and circulating leukocytes are associated with an increased risk of incident
hypertension including a derangement of the renin-angiotensin system, increased oxidative stress,
and downregulation of nitric oxide leading to increased endothelial stiffness and dysfunction (34). A
recent review identified a number of potential sources of extravascular inflammation including
periodontitis as a potential factor influencing vascular risk (32). It is now well documented that patients
with periodontitis have elevated levels of CRP and WBC (7, 35).
In the mediation analysis, our findings suggest that CRP and WBC mediate partly the association
between periodontitis and hypertension, although the effect is rather modest in nature (only 2% of the
association explained by the model for the Korean survey whilst up to 7% in the US survey). Similar
Accepted Article
This article is protected by copyright. All rights reserved
findings were recently reported for CRP (5.4%), WBC (4.2%) and ferritin (10.2%) as mediators of the
total association between a continuous measure of periodontitis and high/uncontrolled BP (≥130/80
mmHg) (36). An alternative pathway implicated in hypertension and cardiovascular injury relates to
the activation of innate and adaptive immune cells such as monocyte/macrophages, and B and T
lymphocytes (37). Damage-activated molecular patterns from the vasculature and Pathogens-
activated molecular patterns from opportunistic diseases such as periodontitis can exacerbate the
inflammatory cascade by activation of Th1 and Th17 lymphocytes, with kidneys and vasculature
injuries aggravating a pro-hypertensive status, which results in progressive raised BP (38, 39).
Our analyses point perhaps towards a more prominent role of the gut and oral microbiome and their
dysbiosis on hypertension (40). Periodontal pathogens may well play a role influencing the gut
microbiome as well as exerting a direct vascular effect. Swallowing gram-negative oral bacteria or
their end-products may trigger metabolic endotoxemia and systemic inflammation contributing to
cardio-metabolic disorders (41). Lastly, experimental studies confirmed that periodontal bacteria can
cause lower nitric oxide bioavailability and vascular dysfunction (42) and patients with periodontitis
exhibit less nitrate-reducing bacteria (43). These novel mechanistic hypotheses warrant further
investigation.
Cross-sectional designs preclude any inference on a possible temporal and/or causal association
between periodontitis and hypertension. In the attempt of mitigating this limitation, we performed the
analysis in two large surveys as to identify common patterns of association and minimizing spurious
findings. Two different periodontal assessments and case definitions were adopted in each survey
which could be considered a limitation but could also show that the association remains significant
irrespectively. While in the NHANES, a recognized case definition was used (19), in the Korean
survey a simplified clinical index (CPI) was selected, which is known to have risks of overestimation of
the extent but underestimation of the prevalence of periodontitis (44). In the attempt to overcome
some of these limitations we included a panel of measures of periodontal lesions to detect whether
simple categorical associations were replicated when using other exposure variables. Another
limitation to consider is the effect of antihypertensive medications on gingival inflammation and
increased probing depths as well as on the overall association between periodontitis and
hypertension (45). Sensitivity analyses were therefore performed by repeating the models in the
group of participants not taking antihypertensive medications. We cannot however exclude that our
Accepted Article
This article is protected by copyright. All rights reserved
analyses missed some common risk determinants for hypertension (abdominal obesity, salt intake,
use of anti-inflammatory drugs, hormone treatments, and stress) as well as unmeasured confounders
associated with both periodontitis and hypertension (residual confounding). Future mechanistic and
clinical studies should investigate further the role of periodontal-driven systemic inflammation and
microbial burden as a risk factor for the development and management of hypertension and its
complications.
Conclusion
Periodontitis is closely linked to hypertension and low-grade inflammation could be a key mediator in
the association. Further interventional studies are needed to ascertain whether the treatment of
periodontitis, leading to a decrease in systemic inflammation, may represent a novel non-
pharmacological intervention in hypertension management.
Acknowledgments: The study was designed and carried out by E Muñoz Aguilera, Y Leira and F
D’Aiuto. These three authors together with Q Miro performed the statistical analyses and interpreted
the results. E Muñoz Aguilera, Y Leira and F D’Aiuto drafted the manuscript. J Nart, M Orlandi, M
Czesnikiewicz-Guzik, TJ. Guzik, AD. Hingorani, provided critical interpretation and revision of the
manuscript. All gave final approval and agreed to be accountable for all aspects of work ensuring
integrity and accuracy.
Sources of Funding: We would like to acknowledge that contribution of this work was undertaken at
UCLH/UCL who received a proportion of funding from the Department of Health’s NIHR Biomedical
Research Centre funding scheme. Dr. Leira holds a Senior Clinical Research Fellowship supported by
the UCL Biomedical Research Centre who receives funding from the NIHR. TJG is funded by
European Research Council (InflammaTENSION; ERC-CoG-726318) and ERA-NET CVD
(PLAQUEFIGHT; 01KL1808 to T.J.G. / NCBiR, Poland)
Patient and Public Involvement:
This research was done without patient involvement. Patients were not invited to comment on the
study design and were not consulted to develop patient relevant outcomes or interpret the results.
Accepted Article
This article is protected by copyright. All rights reserved
Patients were not invited to contribute to the writing or editing of this document for readability or
accuracy.
Disclosures: None
What is already
known about this
subject?
Consistent evidence suggests a direct relationship between periodontitis and
hypertension. Poor oral health is linked to greater systemic inflammation and
increased odds of hypertension. A linear association between systolic blood
pressure and various oral health indices confirm these findings.
What does this
study add?
Periodontitis increases the odds of hypertension by 20-60% in two large
populations and systemic inflammation as assessed by peripheral levels of CRP
and WBC acts as a biological mediator of this association.
How might this
impact on clinical
practice?
Oral health promotion could result in reduced systemic inflammation and it may
represent a novel non-pharmacological intervention in hypertension
management and its complications.
References
1. Zhou B, Bentham J, Di Cesare M, Bixby H, Danaei G, Cowan MJ, et al. Worldwide
trends in blood pressure from 1975 to 2015: a pooled analysis of 1479 population-based
measurement studies with 19· 1 million participants. The Lancet. 2017;389(10064):37-55.
2. Kirkland EB, Heincelman M, Bishu KG, Schumann SO, Schreiner A, Axon RN, et al.
Trends in healthcare expenditures among US adults with hypertension: national estimates,
20032014. Journal of the American Heart Association. 2018;7(11):e008731.
3. Drummond GR, Vinh A, Guzik TJ, Sobey CG. Immune mechanisms of hypertension.
Nature Reviews Immunology. 2019;19(8):517-32.
4. Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS, et al. Update on
prevalence of periodontitis in adults in the United States: NHANES 2009 to 2012. J
Periodontol. 2015;86:611-22.
5. Sanz M, Marco del Castillo A, Jepsen S, Gonzalez‐Juanatey JR, D’Aiuto F, Bouchard P,
et al. Periodontitis and cardiovascular diseases: Consensus report. J Clin Periodontol.
2020;47(3):268-88.
6. Desvarieux M, Demmer RT, Jacobs Jr DR, Rundek T, Boden-Albala B, Sacco RL, et al.
Periodontal bacteria and hypertension: the oral infections and vascular disease
epidemiology study (INVEST). J Hypertens. 2010;28(7):1413.
7. Paraskevas S, Huizinga JD, Loos BG. A systematic review and meta‐analyses on
C‐reactive protein in relation to periodontitis. J Clin Periodontol. 2008;35:277-90.
8. Orlandi M, Suvan J, Petrie A, Donos N, Masi S, Hingorani A, et al. Association
between periodontal disease and its treatment, flow-mediated dilatation and carotid
intima-media thickness: a systematic review and meta-analysis. Atherosclerosis.
2014;236(1):39-46.
Accepted Article
This article is protected by copyright. All rights reserved
9. Tonetti MS, Dyke TE. Periodontitis and atherosclerotic cardiovascular disease:
consensus report of the Joint EFP/AAP Workshop on Periodontitis and Systemic Diseases. J
Clin Periodontol. 2013;40.
10. Preshaw P, Alba A, Herrera D, Jepsen S, Konstantinidis A, Makrilakis K, et al.
Periodontitis and diabetes: a two-way relationship. Diabetologia. 2012;55(1):21-31.
11. Jepsen S, Suvan J, Deschner J. The association of periodontal diseases with metabolic
syndrome and obesity. Periodontology 2000. 2020;83(1):125-53.
12. Muñoz Aguilera E, Suvan J, Buti J, Czesnikiewicz-Guzik M, Barbosa Ribeiro A, Orlandi
M, et al. Periodontitis is associated with hypertension: a systematic review and meta-
analysis. Cardiovasc Res. 2020;116(1):28-39.
13. Czesnikiewicz-Guzik M, Osmenda G, Siedlinski M, Nosalski R, Pelka P, Nowakowski D,
et al. Causal association between periodontitis and hypertension: evidence from Mendelian
randomization and a randomized controlled trial of non-surgical periodontal therapy. Eur
Heart J. 2019;40(42):3459-70.
14. Johnson CL, Paulose-Ram R, Ogden CL, Carroll MD, Kruszan-Moran D, Dohrmann SM,
et al. National health and nutrition examination survey. Analytic guidelines, 1999-2010.
2013.
15. Kweon S, Kim Y, Jang M-j, Kim Y, Kim K, Choi S, et al. Data resource profile: the Korea
national health and nutrition examination survey (KNHANES). Int J Epidemiol. 2014;43(1):69-
77.
16. Ostchega Y, Prineas RJ, Paulose-Ram R, Grim CM, Willard G, Collins D. National
Health and Nutrition Examination Survey 1999-2000: effect of observer training and
protocol standardization on reducing blood pressure measurement error. J Clin Epidemiol.
2003;56(8):768-74.
17. Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo Jr JL, et al. The
seventh report of the joint national committee on prevention, detection, evaluation, and
treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289:2560-71.
18. Mills KT, Bundy JD, Kelly TN, Reed JE, Kearney PM, Reynolds K, et al. Global
disparities of hypertension prevalence and control: a systematic analysis of population-
based studies from 90 countries. Circulation. 2016;134(6):441-50.
19. Eke PI, Page RC, Wei L, Thornton‐Evans G, Genco RJ. Update of the case definitions
for population‐based surveillance of periodontitis. J Periodontol. 2012;83(12):1449-54.
20. Tsakos G, Sabbah W, Hingorani AD, Netuveli G, Donos N, Watt RG, et al. Is
periodontal inflammation associated with raised blood pressure? Evidence from a National
US survey. J Hypertens. 2010;28:2386-93.
21. Masi S, Gkranias N, Li K, Salpea KD, Parkar M, Orlandi M, et al. Association between
short leukocyte telomere length, endotoxemia, and severe periodontitis in people with
diabetes: a cross-sectional survey. Diabetes Care. 2014;37(4):1140-7.
22. Team RC. R: a language and environment for statistical computing. R Foundation for
Statistical Computing, Vienna. http s. www R-proje ct org. 2017.
23. Elliott P, Stamler J, Nichols R, Dyer AR, Stamler R, Kesteloot H, et al. Intersalt
revisited: further analyses of 24 hour sodium excretion and blood pressure within and
across populations. BMJ. 1996;312(7041):1249-53.
24. Collins R, Peto R, MacMahon S, Godwin J, Qizilbash N, Hebert P, et al. Blood
pressure, stroke, and coronary heart disease: part 2, short-term reductions in blood
pressure: overview of randomised drug trials in their epidemiological context. The Lancet.
1990;335(8693):827-38.
Accepted Article
This article is protected by copyright. All rights reserved
25. Stamler J, Stamler R, Neaton JD. Blood pressure, systolic and diastolic, and
cardiovascular risks: US population data. Arch Intern Med. 1993;153(5):598-615.
26. Pietropaoli D, Del Pinto R, Ferri C, Wright Jr JT, Giannoni M, Ortu E, et al. Poor oral
health and blood pressure control among US hypertensive adults: results from the National
Health and Nutrition Examination Survey 2009 to 2014. Hypertension. 2018;72(6):1365-73.
27. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood pressure and risk
of coronary heart disease: the Framingham study. The American journal of cardiology.
1971;27(4):335-46.
28. Domanski M, Mitchell G, Pfeffer M, Neaton JD, Norman J, Svendsen K, et al. Pulse
pressure and cardiovascular diseaserelated mortality: follow-up study of the Multiple Risk
Factor Intervention Trial (MRFIT). JAMA. 2002;287(20):2677-83.
29. Sacks FM, Svetkey LP, Vollmer WM, Appel LJ, Bray GA, Harsha D, et al. Effects on
blood pressure of reduced dietary sodium and the Dietary Approaches to Stop Hypertension
(DASH) diet. N Engl J Med. 2001;344(1):3-10.
30. Neter JE, Stam BE, Kok FJ, Grobbee DE, Geleijnse JM. Influence of weight reduction
on blood pressure: a meta-analysis of randomized controlled trials. Hypertension.
2003;42(5):878-84.
31. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure: a meta-
analysis of randomized, controlled trials. Ann Intern Med. 2002;136(7):493-503.
32. Libby P, Loscalzo J, Ridker PM, Farkouh ME, Hsue PY, Fuster V, et al. Inflammation,
immunity, and infection in atherothrombosis: JACC review topic of the week. J Am Coll
Cardiol. 2018;72(17):2071-81.
33. Ridker PM, MacFadyen JG, Everett BM, Libby P, Thuren T, Glynn RJ, et al.
Relationship of C-reactive protein reduction to cardiovascular event reduction following
treatment with canakinumab: a secondary analysis from the CANTOS randomised controlled
trial. The Lancet. 2018;391(10118):319-28.
34. Guzik TJ, Touyz RM. Oxidative Stress, Inflammation, and Vascular Aging in
Hypertension. Hypertension. 2017;70(4):660-7. doi:
10.1161/HYPERTENSIONAHA.117.07802. PubMed PMID: 28784646.
35. Loos BG. Systemic markers of inflammation in periodontitis. J Periodontol.
2005;76:2106-15.
36. Pietropaoli D, Del Pinto R, Ferri C, Marzo G, Giannoni M, Ortu E, et al. Association
between periodontal inflammation and hypertension using periodontal inflamed surface
area and bleeding on probing. J Clin Periodontol. 2020;47(2):160-72.
37. Guzik TJ, Hoch NE, Brown KA, McCann LA, Rahman A, Dikalov S, et al. Role of the T
cell in the genesis of angiotensin IIinduced hypertension and vascular dysfunction. J Exp
Med. 2007;204(10):2449-60.
38. Krishnan SM, Ling YH, Huuskes BM, Ferens DM, Saini N, Chan CT, et al.
Pharmacological inhibition of the NLRP3 inflammasome reduces blood pressure, renal
damage, and dysfunction in salt-sensitive hypertension. Cardiovasc Res. 2019;115(4):776-
87.
39. Wang H-X, Li W-J, Hou C-L, Lai S, Zhang Y-L, Tian C, et al. CD1d-dependent natural
killer T cells attenuate angiotensin II-induced cardiac remodelling via IL-10 signalling in mice.
Cardiovasc Res. 2019;115(1):83-93.
40. Santisteban MM, Qi Y, Zubcevic J, Kim S, Yang T, Shenoy V, et al. Hypertension-linked
pathophysiological alterations in the gut. Circ Res. 2017;120(2):312-23.
Accepted Article
This article is protected by copyright. All rights reserved
41. Arimatsu K, Yamada H, Miyazawa H, Minagawa T, Nakajima M, Ryder MI, et al. Oral
pathobiont induces systemic inflammation and metabolic changes associated with
alteration of gut microbiota. Sci Rep. 2014;4:4828.
42. Velsko IM, Chukkapalli SS, Rivera MF, Lee J-Y, Chen H, Zheng D, et al. Active invasion
of oral and aortic tissues by Porphyromonas gingivalis in mice causally links periodontitis
and atherosclerosis. PLoS One. 2014;9(5).
43. Ashworth A, Cutler C, Farnham G, Liddle L, Burleigh M, Rodiles A, et al. Dietary intake
of inorganic nitrate in vegetarians and omnivores and its impact on blood pressure, resting
metabolic rate and the oral microbiome. Free Radic Biol Med. 2019;138:63-72.
44. Tran DT, Gay I, Du XL, Fu Y, Bebermeyer RD, Neumann AS, et al. Assessment of
partial‐mouth periodontal examination protocols for periodontitis surveillance. J Clin
Periodontol. 2014;41(9):846-52.
45. Rodrigues M, Barbirato D, Luiz R, Scharfstein J, Salles G, Feres‐Filho E. Effect of
antihypertensive therapy with angiotensin‐converting enzyme inhibitors on chronic
periodontitis: a casecontrol study. Oral Dis. 2016;22(8):791-6.
Corresponding author:
Prof. Francesco D’Aiuto
Periodontology Department, UCL Eastman Dental Institute
21 University Street, London, WC1E 6DE
Email: f.daiuto@ucl.ac.uk
Accepted Article
1
Figure 2: Mediation analysis model
A. NHANES
Mediation models of periodontitis, inflammation and hypertension (unadjusted) in NHANES (N=3460):
Route 1: Direct effect (0.150; p<0.001) of Periodontitis (exposure) towards Hypertension (outcome).
Route 2: Indirect effect (0.342; p<0.001) of Periodontitis (exposure) towards WBC (mediator) is shown, but no
effect (0.004; p=0.193) is observed in the last step of the model from WBC (mediator) towards Hypertension
(outcome).
Route 3: Indirect effect (0.18; p<0.001), of Periodontitis (exposure) is observed towards Log CRP (mediator) and
an effect (0.054; p<0.001), from Log CRP (mediator) towards Hypertension (outcome).
Route 4: Indirect effect (0.342; p<0.001) of Periodontitis (exposure) towards WBC (mediator) and an effect
(0.105; p<0.001) from WBC towards Log CRP (mediator) and an effect (0.054; p<0.001) from the Log CRP
(mediator) towards Hypertension (outcome).
B. K-NHANES
Mediation models of periodontitis, inflammation and hypertension (unadjusted) in K-NHANES (N=4539):
Route 1: Direct effect (0.193; p<0.001) of Periodontal index (exposure) towards Hypertension (outcome).
Route 2: Indirect effect (0.285; p<0.001) of Periodontal index (exposure) towards WBC (mediator), and an effect
(0.015; p<0.001) from WBC (mediator) towards Hypertension (outcome).
Route 3: Indirect effect (0.224; p=0.003), of Periodontal index (exposure) is observed towards Log CRP
(mediator) and an effect (0.012; p<0.001), from Log CRP (mediator) towards Hypertension (outcome).
Route 4: Indirect effect (0.285; p<0.001) of Periodontal index (exposure) towards WBC (mediator) and an effect
(0.237; p<0.001) from WBC towards Log CRP (mediator) and an effect (0.012; p<0.001) from the Log CRP
(mediator) towards Hypertension (outcome).
... Analysis of large registries further supports these conclusions. Munoz Aguilera et al. [14] have provided evidence that periodontitis increases the odds of hypertension by 20%-60% in large populations from surveys based in the USA (n = 3460) and Korea (n = 4539). Periodontitis was related to the occurrence of hypertension and higher systolic blood pressure (SBP) compared to people without periodontitis. ...
... Systemic inflammatory cytokines and CRP serve as biomarkers linking periodontitis and hypertension ( Figure 1). The mediation analysis in large epidemiological survey studies discussed above has suggested that CRP and white blood cell counts (WBC) mediated partly the association between periodontitis and hypertension [14]. Similar results were observed in another population [29]. ...
... Recently published studies have provided evidence that periodontitis, as a chronic inflammatory disease, is associated with the prevalence of hypertension [5,[13][14][15][16][17][30][31][32]. Poor oral health is linked to systemic inflammation and increased probability of the development of hypertension. ...
Article
Hypertension and periodontitis are both highly prevalent co-morbidities worldwide, and their occurrence increases with age. Multiple observational epidemiological studies have shown that periodontitis is associated with an increased cardiovascular disease (CVD) occurrence. Large systematic reviews and metanalyses further show that periodontitis increases the risk of hypertension and is associated with increased systolic and diastolic blood pressure. Genetic and clinical evidence, utilizing mendelian randomization and randomized clinical trials, support the causal role of periodontitis in hypertension. The mechanisms of this link remain unclear. Critical components of immune and inflammatory pathogenesis of periodontitis considerably overlap with immune mechanisms of hypertension. Clinical studies support that both C-reactive protein (CRP) levels and white blood cell counts (WBC) mediate the relationship between periodontal disease and high blood pressure. In particular, activation of Th1, Th17, T regulatory cells, and proinflammatory monocytes has been shown to be essential in both conditions. Immunosenescent dysregulated CD28null T cells have been implicated, along with key effector cytokines such as interleukin 6 (IL-6), TNF-alpha (TNF-α), interferon-gamma (IFN-γ), and interleukin 17 (IL-17). A better understanding of the relationships between hypertension and periodontitis is essential not only for possible utilization of this knowledge for a non-pharmacological approach to improving blood pressure control. It may also provide valuable pathogenetic clues linking inflammation and hypertension, which has become particularly relevant in the light of links between hypertension and autoimmune disorders or, more recently, COVID-19.
... A possible causal relationship has been proposed using Mendelian randomization-a reliable test of causality between risk factors and phenotypes-studied in the UK-Biobank and International Consortium for Blood pressure (ICBP)-Genome Wide Association Study (GWAS) datasets (including 750 000 participants) (16). This study confirmed a link between genetic variants to periodontitis (as approximate lifetime exposure to PD) and BP phenotypes (17). ...
... Nevertheless, the exact mechanisms involved in the association between Periodontitis and HBP remain unknown (17). Clinical and experimental studies have suggested plausible mechanisms related to: local and systemic inflammation, the microbial effect on the vascular system, the host immune response and the specific type of cell activation (18). ...
Article
Full-text available
Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. High blood pressure in particular, continues to increase throughout the global population at an increasingly fast pace. The relationship between arterial hypertension and periodontitis has been recently discussed in the context of its origins and implications. Particularly relevant is the role of the periodontal microbiome linked to persistent local and systemic inflammation, along with other risk factors and social determinants of health. The present protocol will investigate/assess the association between periodontal disease and its microbiome on the onset of hypertension, within a cohort from Mexico City. One thousand two hundred twelve participants will be studied during a 60-month period. Studies will include analysis of periodontal conditions, sampling and sequencing of the salivary and subgingival microbiome, interviews on nutritional and lifestyle habits, social determinants of health, blood pressure and anthropometric measurements. Statistical associations and several classic epidemiology and machine learning approaches will be performed to analyze the data. Implications for the generation of public policy—by early public health interventions or epidemiological surveillance approaches—and for the population empowerment—via the establishment of primary prevention recommendations, highlighting the relationship between oral and cardiovascular health—will be considered. This latter set of interventions will be supported by a carefully planned science communication and health promotion strategy. This study has been registered and approved by the Research and Ethics Committee of the School of Dentistry, Universidad Nacional Autónoma de México (CIE/0308/05/2019) and the National Institute of Genomic Medicine (CEI/2020/12). The umbrella cohort was approved by the Institutional Bioethics Committee of the National Institute of Cardiology-Ignacio Chavez (INC-ICh) under code 13-802.
... A cross-sectional study from Thailand revealed CRP (5.2%) and white blood count (19.1%) are mediators of the relationship between periodontitis and impaired fasting glucose (49). The significant indirect effect of periodontal infection on hypertension mediated through CRP was determined via two national databases (50). ...
Article
Full-text available
AimThis investigation explored the relationship between oral bacteria and metabolic syndrome (METS).Materials and Methods There were 4,882 subjects enrolled in this cross-sectional study from the NHANES III database. The severity of periodontitis was classified into mild, moderate and severe. We measured oral bacterial antibodies. We examined the relationship between serum immunoglobulin G (IgG) antibodies of oral bacteria and METS via performing multivariate regression analysis. Mediation analysis of oral bacteria on the correlation between periodontitis and METS was also executed.ResultsAfter adjusting for covariates, the serum IgG antibodies of P. nigrescens, E. corrodens, and E. nodatum were associated with the presence of METS (p = 0.006, p = 0.014 and p = 0.018, respectively). Furthermore, serum IgG antibodies of P. intermedia, T. forsythia and V. parvula were positively associated with the presence of METS (p = 0.001, p = 0.011, and p = 0.002, respectively) and ≥4 features of METS (p = 0.019, p = 0.025, and p = 0.02, respectively). P. intermedia IgG mediated 11.2% of the relationship between periodontitis and METS.Conclusion Serological markers of oral pathogens were correlated with the presence and the number of METS features after multivariable adjustment. Oral bacteria acted as a mediator of the correlation between periodontitis and METS. Our study provided a biologically plausible explanation for the association between periodontitis and METS, which provides a comprehensive evaluation of periodontitis.
... There have been other efforts to analyze the relationship between PD and hypertension (Pietropaoli et al., 2020). Two large surveys were analyzed in this regard by Leira et al. (2020b). Unsurprisingly, the authors found that systemic inflammatory states were at the center connecting the two conditions. ...
Article
Full-text available
Periodontitis is a common inflammatory disease of infectious origins that often evolves into a chronic condition. Aside from its importance as a stomatologic ailment, chronic periodontitis has gained relevance since it has been shown that it can develop into a systemic condition characterized by unresolved hyper-inflammation, disruption of the innate and adaptive immune system, dysbiosis of the oral, gut and other location's microbiota and other system-wide alterations that may cause, coexist or aggravate other health issues associated to elevated morbi-mortality. The relationships between the infectious, immune, inflammatory, and systemic features of periodontitis and its many related diseases are far from being fully understood and are indeed still debated. However, to date, a large body of evidence on the different biological, clinical, and policy-enabling sources of information, is available. The aim of the present work is to summarize many of these sources of information and contextualize them under a systemic inflammation framework that may set the basis to an integral vision, useful for basic, clinical, and therapeutic goals.
... In order to assess the systemic health status of the study participants, the total number of chronic medical conditions was considered as a continuous variable for the purpose of data handling and was reached upon analysis of self-report of asthma, psoriasis, gout, congestive heart failure, coronary heart disease, angina, heart attack, stroke, emphysema, thyroid, bronchitis, liver disease and cancer. Diabetes mellitus (DM) and hypertension were separately appraised variables due to their known strong impact on oral health [35][36][37][38]. DM was defined through a previous report and confirmed with Hba1c values (>6.5%) [39]. ...
Article
Full-text available
Objectives: To evaluate tooth loss severity in PD patients and the impact of missing teeth on blood pressure (BP) and glycated hemoglobin (Hba1c) levels. Methods: All adults reporting specific PD medication regimens with complete dental examinations were included from the NHANES 2001 to 2018 databases. Sociodemographic, systolic BP (SBP), diastolic BP (DBP) and Hba1c data were compared according to tooth loss severity, and linear regression analyses on the impact of tooth loss on SBP, DBP and Hba1c levels were conducted. Results: The 214 included participants presented 9.7 missing teeth, 23.8% severe tooth loss and 18.2% total edentulousness. Severe tooth loss cases were significantly older (p < 0.001), had higher smoking prevalence (p = 0.008), chronic medical conditions (p = 0.012) and higher Hba1c (p = 0.001), SBP (p = 0.015) and DBP (p < 0.001) levels. Crude and adjusted linear models revealed a relationship between SBP, DBP and missing teeth; however, age confounded these links (SBP: B = 0.10, SE = 0.16, p < 0.05; DBP: B = 0.16, SE = 0.10, p < 0.05). Tooth loss presented no significant relationship with Hba1c levels. Conclusions: Severe tooth loss is prevalent among PD patients. Blood pressure levels showed a positive linear relationship with the number of missing teeth, although age was a confounding factor. Furthermore, tooth loss and Hba1c levels revealed no significant linear relationship.
... These results are in partial disagreement with a recent analysis of cross-sectional data, based on national health surveys in US and Korea, where a 2% to 7% mediating effect of WBC and CRP was observed when examining the association between periodontitis and hypertension. 32 A possible explanation for these differences relates to an overall younger population of this study sample (35 years old) versus 51 and 46 years old in the American and Korean populations, and possibly due to the systemically healthy status of this sample, when compared with representative samples of those populations, including systemic conditions. Nevertheless, an association of arterial BP with both continuous and categorical measures of periodontitis in younger and systemically healthy individuals strengthens the evidence in favor of a causal association between the two diseases. ...
Article
Recent evidence suggests hypertension and periodontitis are closely linked but limited data is available on the nature of the association. We aimed to investigate the relationship between periodontitis and mean arterial blood pressure in a sample of otherwise systemically healthy individuals. A case-control study including 250 cases (participants with periodontitis) and 250 controls (without periodontitis) was designed from a register of clinical trials conducted between 2000 and 2018 in a university setting. Cases were age, sex, and body mass index balanced with controls. Linear, logistic regression, and mediation models were planned to test the association between various periodontal measures and arterial blood pressure. We further investigated the role of systemic inflammation assessed by hs-CRP (high-sensitivity C-reactive protein) and white cell counts. Cases presented with 3.36 mm Hg (95% CI, 0.91–5.82, P =0.007) higher mean systolic blood pressure and 2.16 mm Hg (95% CI, 0.24–4.08, P =0.027) higher diastolic blood pressure than controls. Diagnosis of periodontitis was associated with mean systolic blood pressure (β=3.46±1.25, P =0.005) and greater odds of systolic blood pressure ≥140 mm Hg (odds ratio, 2.3 [95% CI, 1.15–4.60], P =0.018) independent of common cardiovascular risk factors. Similar findings were observed when continuous measures of periodontal status were modeled against systolic blood pressure. Measures of systemic inflammation although elevated in periodontitis were not found to be mediators of the association between periodontitis and arterial blood pressure values. Periodontitis is linked to higher systolic blood pressure in otherwise healthy individuals. Promotion of periodontal and systemic health strategies in the dental and medical setting could help reduce the burden of hypertension and its complications.
... To assess participant's systemic status, we considered the number of self-reported medical conditions as an aggregate continuous variable to note the presence of asthma, congestive heart failure, coronary heart disease, angina, stroke, heart attack, emphysema, overweight, bronchitis, liver conditions, thyroid conditions and cancer. Considering the strong association of hypertension [38] and diabetes [39,40] with periodontitis in the NHANES, we included these variables separately. The presence of hypertension was defined according to the presence of average systolic blood pressure > 140 mmHg or average diastolic blood pressure > 90 mmHg [41]. ...
Article
Full-text available
Patients suffering from periodontitis are at a higher risk of developing cognitive dysfunction. However, the mediation effect of an inflammatory diet and serum vitamin D levels in this link is unclear. In total, 2062 participants aged 60 years or older with complete periodontal diagnosis and cognitive tests from the National Health and Nutrition Examination Survey (NHANES) 2011-2012 and 2013-2014 were enrolled. The Consortium to Establish a Registry for Alzheimer's disease (CERAD) word learning subtest (WLT) and CERAD delayed recall test (DRT), the animal fluency test (AFT) and the digit symbol substitution test (DSST) was used. Dietary inflammatory index (DII) was computed via nutrition datasets. Mediation analysis tested the effects of DII and vitamin D levels in the association of mean probing depth (PD) and attachment loss (AL) in all four cognitive tests. Periodontitis patients obtained worse cognitive test scores than periodontally healthy individuals. DII was negatively associated with CERAD-WLT, CERAD-DRT, AFT and DSST, and was estimated to mediate between 9.2% and 36.4% of the total association between periodontitis with cognitive dysfunction (p < 0.05). Vitamin D showed a weak association between CERAD-DRT, AFT and DSST and was estimated to between 8.1% and 73.2% of the association between periodontitis and cognitive dysfunction (p < 0.05). The association between periodontitis and impaired cognitive function seems to be mediated both by a proinflammatory dietary load and vitamin D deficiency. Future studies should further explore these mediators in the periodontitis-cognitive decline link.
Article
Aims: Recent evidence suggests that periodontitis causes hypertension, which is a precursor to development of other systemic diseases. The aim of this study was to examine the effect of hypertension and periodontitis on the risk of subsequent systemic disease. Materials and methods: This longitudinal cohort study included 244,393 UK Biobank participants who were free of systemic disease other than hypertension at baseline. Self-reported responses of painful gums or loose teeth were surrogates for periodontitis. Hypertensives were identified by clinical diagnosis, or elevated blood pressure (> = 140/90 mmHg). Systemic diseases including cancer, cardiovascular disease and diabetes were identified from linked diagnostic codes. Multivariable Cox proportional hazard models were used to quantify the risk of systemic diseases and all-cause mortality, stratified by hypertensive and periodontitis status. Results: The average age of the study population was 55.4 (standard deviation[SD:] 8.1) years, and 130,220 (53.3%) participants were female. At baseline, 131,566 (53.8%) participants were hypertensive and 4.5% reported periodontitis. The incidence rates of all systemic diseases were higher in hypertensive than non-hypertensive participants of the same periodontitis status. In hypertensives, an additive effect was observed for periodontitis on the risks of cardiovascular disease (adjusted hazard ratio[HR]: 1.35, 95% confidence interval[CI]: 1.21-1.53) and respiratory disease (HR: 1.11, 95% CI: 0.95-1.30) compared to hypertensive healthy controls. Conclusion(s): Hypertensives with periodontitis have exacerbated risks of several systemic diseases. Future interventional studies should consider the effect of periodontal treatment on systemic outcomes in targeted hypertensive populations. This article is protected by copyright. All rights reserved.
Article
Full-text available
Periodontitis is a multifactorial chronic inflammatory disease associated with dysbiotic plaque biofilms and characterized by progressive destruction of the tooth‐supporting apparatus. Globally, it is estimated that 740 million people are affected by its severe form. Periodontitis has been suggested to be linked to obesity and metabolic syndrome. Obesity, defined as excessive fat accumulation, is a complex multifactorial chronic inflammatory disease, with a high and increasing prevalence. Metabolic syndrome is defined as a cluster of obesity, dyslipidemia, hypertension, and dysglycemia. Obesity, metabolic syndrome and periodontitis are among the most common non‐communicable diseases and a large body of evidence from epidemiologic studies supports the association between these conditions. Extensive research has established plausible mechanisms to explain how these conditions can negatively impact each other, pointing to a bidirectional adverse relationship. At present there is only limited evidence available from a few intervention studies. Nevertheless, the global burden of periodontitis combined with the obesity epidemic has important clinical and public health implications for the dental team. In accordance with the common risk factor approach for tackling non‐communicable diseases, it has been proposed that oral healthcare professionals have an important role in the promotion of periodontal health and general well‐being through facilitation of healthy lifestyle behaviours.
Article
Full-text available
Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations. Results and conclusions: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices.
Article
Full-text available
Background: In Europe cardiovascular disease (CVD) is responsible for 3.9 million deaths (45% of deaths), being ischaemic heart disease, stroke, hypertension (leading to heart failure) the major cause of these CVD related deaths. Periodontitis is also a chronic non-communicable disease (NCD) with a high prevalence, being severe periodontitis, affecting 11.2% of the world's population, the sixth most common human disease. Material and methods: There is now a significant body of evidence to support independent associations between severe periodontitis and several NCDs, in particular CVD. In 2012 a joint workshop was held between the European Federation of Periodontology (EFP) and the American Academy of Periodontology to review the literature relating periodontitis and systemic diseases, including CVD. In the last five years important new scientific information has emerged providing important emerging evidence to support these associations RESULTS AND CONCLUSIONS: The present review reports the proceedings of the workshop jointly organised by the EFP and the World Heart Federation (WHF), which has updated the existing epidemiological evidence for significant associations between periodontitis and CVD, the mechanistic links and the impact of periodontal therapy on cardiovascular and surrogate outcomes. This review has also focused on the potential risk and complications of periodontal therapy in patients on anti thrombotic therapy and has made recommendations for dentists, physicians and for patients visiting both the dental and medical practices.
Article
Full-text available
Recent evidence suggests a link between periodontitis (PD) and hypertension, but the nature of this association remains unclear. The overall aim of this review was to critically appraise the evidence linking these two common disorders. Systematic search was conducted for studies published up to December 2018. Prevalence of hypertension in patients with PD (moderate/severe groups) vs. those without PD (non-PD) was the primary outcome. Additional outcomes included adjusted mean difference in systolic (SBP) and diastolic (DBP) blood pressure (BP) levels in PD vs. non-PD, assessment of biomarkers in PD and hypertension, and BP changes after periodontal therapy. From 81 studies selected, 40 were included in quantitative meta-analyses. Diagnoses of moderate-severe PD [odds ratio (OR) = 1.22; 95% confidence interval (CI): 1.10-1.35] and severe PD (OR = 1.49; 95% CI: 1.09-2.05) were associated with hypertension. Prospective studies confirmed PD diagnosis increased likelihood of hypertension occurrence (OR = 1.68; 95% CI: 0.85-3.35). Patients with PD exhibited higher mean SBP [weighted mean difference (WMD) of 4.49 mmHg; 95% CI: 2.88-6.11] and DBP (2.03 mmHg; 95% CI: 1.25-2.81) when compared with non-PD. Lastly, only 5 out of 12 interventional studies confirmed a reduction in BP following periodontal therapy, ranging from 3 to 12.5 mmHg of SBP and from 0 to 10 mmHg of DBP. PD is associated with increased odds of hypertension (SORT C) and higher SBP/DBP levels. The evidence suggesting that PD therapy could reduce BP is inconclusive. Although additional research is warranted on this association, these results suggest that oral health assessment and management of PD could not only improve oral/overall health and quality of life but also be of relevance in the management of patients with hypertension.
Article
Full-text available
Aim: Periodontitis is a relapsing-remitting disease. Compared to bleeding on probing (BoP), expression of disease activity, periodontal inflamed surface area (PISA) incorporates chronic disease parameters. We tested the association of PISA and BoP with blood pressure (BP) in NHANES III. Materials and methods: 8,614 subjects (≥30y) with complete periodontal and BP examinations were enrolled. PISA was derived from periodontal probing depth and BoP. The association of PISA and BoP with high/uncontrolled BP was examined by multiple-adjusted models. Inflammatory markers were tested as possible mediators. A machine learning (ML) approach was used to define the relative importance of PISA and BoP and estimate the power of BP status prediction. Results: Compared to no inflammation, severe PISA and BoP were associated with 43% (p<0.001) and 32% (p=0.006) higher odds of high/uncontrolled BP (≥130/80 mmHg), and with higher systolic BP by ≈4 (p<0.001) and 5 (p<0.001) mmHg, respectively. Inflammatory markers appeared to mediate this association to various extents, without threshold effect. BoP predicted high/uncontrolled BP more efficiently than PISA using ML. Conclusion: PISA and BoP describe the association of periodontal inflammation and hypertension with subtle differences. The contribution of local inflammation to the global inflammatory burden might explain the observed findings.
Article
Full-text available
Aims Inflammation is an important driver of hypertension. Periodontitis is a chronic inflammatory disease, which could provide a mechanism for pro-hypertensive immune activation, but evidence of a causal relationship in humans is scarce. We aimed to investigate the nature of the association between periodontitis and hypertension. Methods and results We performed a two-sample Mendelian randomization analysis in the ∼750 000 UK-Biobank/International Consortium of Blood Pressure-Genome-Wide Association Studies participants using single nucleotide polymorphisms (SNPs) in SIGLEC5, DEFA1A3, MTND1P5, and LOC107984137 loci GWAS-linked to periodontitis, to ascertain their effect on blood pressure (BP) estimates. This demonstrated a significant relationship between periodontitis-linked SNPs and BP phenotypes. We then performed a randomized intervention trial on the effects of treatment of periodontitis on BP. One hundred and one hypertensive patients with moderate/severe periodontitis were randomized to intensive periodontal treatment (IPT; sub- and supragingival scaling/chlorhexidine; n = 50) or control periodontal treatment (CPT; supragingival scaling; n = 51) with mean ambulatory 24-h (ABPM) systolic BP (SBP) as primary outcome. Intensive periodontal treatment improved periodontal status at 2 months, compared to CPT. This was accompanied by a substantial reduction in mean SBP in IPT compared to the CPT (mean difference of −11.1 mmHg; 95% CI 6.5–15.8; P < 0.001). Systolic BP reduction was correlated to periodontal status improvement. Diastolic BP and endothelial function (flow-mediated dilatation) were also improved by IPT. These cardiovascular changes were accompanied by reductions in circulating IFN-γ and IL-6 as well as activated (CD38+) and immunosenescent (CD57+CD28null) CD8+T cells, previously implicated in hypertension. Conclusion A causal relationship between periodontitis and BP was observed providing proof of concept for development of clinical trial in a large cohort of hypertensive patients. ClinicalTrials.gov: NCT02131922.
Article
Full-text available
Periodontal disease is a chronic inflammatory disorder of the tissues surrounding the teeth, with evidence of systemic effects. Some studies showed the benefit of periodontal therapy on blood pressure (BP), but the impact of periodontitis on BP control is unknown. We retrospectively analyzed cross-sectional, nationally representative data from treated hypertensive adults aged ≥30 years with and without periodontitis. BP was examined as both continuous (mm Hg) and categorical (treatment goal achievement status according to guidelines: at goal and above goal) variable according to the presence or absence of periodontitis and its clinical parameters (probing depth, clinical attachment loss, and disease severity [mild, moderate, and severe]). Systolic BP means and odds ratios for uncontrolled BP according to the presence and severity of periodontitis were calculated using progressively adjusted models. Among treated hypertensive adults, mean systolic BP was about 2.3 to 3 mm Hg higher in the presence of periodontitis (P<0.0001). Periodontitis was associated with unsuccessful antihypertensive treatment after multiple adjustments, with higher odds by disease severity. A good periodontal health is associated with better systolic BP profile during antihypertensive therapy by about 2.3 to 3 mm Hg and with lower odds of antihypertensive treatment failure. Dedicated studies are needed to test the impact of periodontal therapy on BP and the long-term effects on cardiovascular outcomes of this complementary approach to systemic health.
Article
Recent evidence suggests a link between periodontitis (PD) and hypertension, but the nature of this association remains unclear. The overall aim of this review was to critically appraise the evidence linking these two common disorders. Systematic search was conducted for studies published up to December 2018. Prevalence of hyperten- sion in patients with PD (moderate/severe groups) vs. those without PD (non-PD) was the primary outcome. Additional outcomes included adjusted mean difference in systolic (SBP) and diastolic (DBP) blood pressure (BP) levels in PD vs. non-PD, assessment of biomarkers in PD and hypertension, and BP changes after periodontal ther- apy. From 81 studies selected, 40 were included in quantitative meta-analyses. Diagnoses of moderate-severe PD [odds ratio (OR)=1.22; 95% confidence interval (CI): 1.10–1.35] and severe PD (OR=1.49; 95% CI: 1.09–2.05) were associated with hypertension. Prospective studies confirmed PD diagnosis increased likelihood of hyperten- sion occurrence (OR = 1.68; 95% CI: 0.85–3.35). Patients with PD exhibited higher mean SBP [weighted mean dif- ference (WMD) of 4.49 mmHg; 95% CI: 2.88–6.11] and DBP (2.03 mmHg; 95% CI: 1.25–2.81) when compared with non-PD. Lastly, only 5 out of 12 interventional studies confirmed a reduction in BP following periodontal therapy, ranging from 3 to 12.5 mmHg of SBP and from 0 to 10 mmHg of DBP. PD is associated with increased odds of hypertension (SORT C) and higher SBP/DBP levels. The evidence suggesting that PD therapy could reduce BP is in- conclusive. Although additional research is warranted on this association, these results suggest that oral health assessment and management of PD could not only improve oral/overall health and quality of life but also be of rele- vance in the management of patients with hypertension.
Article
Vegetarian diets are commonly associated with lower blood pressure levels. This has been related to greater consumption of inorganic nitrate, since vegetables are the main source of this anion. Dietary nitrate is reduced to nitrite by commensal bacteria in the mouth, which in turn leads to increased circulatory nitrite availability. Nitrite can form nitric oxide by several pathways promoting a reduction in the vascular tone and lower blood pressure. This study tested whether vegetarians have higher concentrations of nitrite in saliva and plasma, and lower blood pressure and resting metabolic rate (RMR), due to higher intakes of nitrate, compared to omnivores. Following a non-randomized, cross-over and single-blinded design we measured dietary nitrate intake, blood pressure and RMR in young and healthy vegetarians (n = 22) and omnivores (n = 19) with similar characteristics after using placebo or antibacterial mouthwash for a week to inhibit oral bacteria. Additionally, we analyzed salivary and plasma nitrate and nitrite concentrations, as well as the oral nitrate-reduction rate and oral microbiome in both groups. Dietary nitrate intake in vegetarians (97 ± 79 mg/day) was not statistically different (P > 0.05) to omnivores (78 ± 47 mg/day). Salivary and plasma nitrate and nitrite concentrations were similar after placebo mouthwash in both groups (P > 0.05). The oral nitrate-reducing capacity, abundance of oral bacterial species, blood pressure and RMR were also similar between vegetarians and omnivores (P > 0.05). Antibacterial mouthwash significantly decreased abundance of oral nitrate-reducing bacterial species in vegetarians ( _ 16.9%; P < 0.001) and omnivores ( _ 17.4%; P < 0.001), which in turn led to a significant reduction of the oral nitrate-reducing capacity in vegetarians (−78%; P < 0.001) and omnivores (−85%; P < 0.001). However, this did not lead to a significant increase in blood pressure and RMR in either groups (P > 0.05). These findings suggest that vegetarian diets may not alter nitrate and nitrite homeostasis, or the oral microbiome, compared to an omnivore diet. Additionally, inhibition of oral nitrite synthesis for a week with antibacterial mouthwash did not cause a significant raise in blood pressure and RMR in healthy, young individuals independent of diet.
Article
Hypertension affects 30% of adults and is the leading risk factor for heart attack and stroke. Traditionally, hypertension has been regarded as a disorder of two systems that are involved in the regulation of salt–water balance and cardiovascular function: the renin–angiotensin–aldosterone system (RAAS) and the sympathetic nervous system (SNS). However, current treatments that aim to limit the influence of the RAAS or SNS on blood pressure fail in ~40% of cases, which suggests that other mechanisms must be involved. This Review summarizes the clinical and experimental evidence supporting a contribution of immune mechanisms to the development of hypertension. In this context, we highlight the immune cell subsets that are postulated to either promote or protect against hypertension through modulation of cardiac output and/or peripheral vascular resistance. We conclude with an appraisal of knowledge gaps still to be addressed before immunomodulatory therapies might be applied to at least a subset of patients with hypertension. © 2019, The Author(s), under exclusive licence to Springer Nature Limited.