International Dental Journal (2009) 59, 197-209

Periodontal diseases and

cardiovascular events: meta-
analysis of observational studies
Alessandra Blaizot, Jean-Noël Vergnes, Samer Nuwwareh, Jacques
Amar and Michel Sixou
Toulouse, France

Objective: Many studies have investigated the relationship between periodontal and car-
diovascular diseases but their results are heterogeneous. Meta-analyses were conducted
to examine the association between exposure to periodontitis and cardiovascular diseases.
Material and methods: Studies published between 1989 and 2007 were retrieved from
seven databases. The included articles reported the results from observational studies
(cohort, cross-sectional and case-control studies) and assessed the link between peri-
odontal exposure and cardiovascular diseases as confirmed by one of the following criteria:
diagnosed coronary artery disease, angina pectoris, acute myocardial infarction, mortality
caused by cardiac pathology. The study characteristics were abstracted by independent
researchers following a standardised protocol. The MOOSE guidelines for meta-analysis of
observational studies were followed. Results: From 215 epidemiological studies, 47 were
observational, of which 29 articles could be combined by the meta-analysis methodology.
The pooled odds ratio calculated from the 22 case-control and cross-sectional studies
was 2.35 (95% CI [1.87; 2.96], p< 0.0001). The risk of developing cardiovascular disease
was found to be significantly (34%) higher in subjects with periodontal disease compared
to those without periodontal disease (pooled relative risk from the 7 cohort studies was
1.34 (95% CI [1.27; 1.42], p< 0.0001). Conclusions: It seems from observational studies
that subjects with periodontal diseases have higher odds and higher risks of developing
cardiovascular diseases but the reduction in the risk of cardiovascular events associated
with the treatment of periodontitis remains to be investigated.

Key words: Cardiovascular diseases, periodontitis, observational studies, meta-analysis,

systematic review

Cardiovascular diseases, including acute myocardial
infarction and angina pectoris, are a major health prob-
lem in most western countries. Annual mortality from
cardiovascular diseases is about 12 million cases/year1,
and cardiovascular diseases are responsible for 30% of
all deaths in the United States2,3. According to current
trends in the United States, half the healthy 40-year-old
males and one third of healthy 40-year-old females will
develop a cardiovascular disease in the future4.
While many risk factors, like age, gender, diabetes,
cholesterol level and tobacco smoking, are well es-
tablished5, other factors are still not well understood,
among them the role of periodontitis. Periodontal
disease (PD) is a chronic inflammation of tooth sup-
© 2009 FDI/World Dental Press
0020-6539/09/04197-13
port tissues caused by microbial invasion. Various
mechanisms have been proposed to explain the potential
relationship between PD and cardiovascular diseases.
They are mainly of two types: external factors that can
affect both diseases independently, such as tobacco6, or
a suspected direct causal effect of PD. This suspicion
is based on several fundamental studies that suggest
systemic infection7, inflammation8 and autoimmunity
induction9 as possible physiopathologies.
Epidemiological studies show conflicting relations
between PD and cardiovascular diseases. Some studies
have reported that PD is significantly associated with
cardiovascular diseases as a risk factor10-12, while others
have failed to show such a correlation13-15. Interventional
doi:10.1922/IDJ_2114Sixou13
198
studies trying to explain this relationship generally use
C-reactive protein as the major cardiac outcome with
statistical methods unsuitable for its skewed distribu-
tion16. For this reason, the interpretation and use of
these results are questionable.
The aim of the present study was to perform meta-
analyses of observational studies examining the risk
of cardiovascular diseases with PD exposure in a large
panel of population.
Methods
The MOOSE guidelines17 for meta-analysis of observa-
tional studies were followed.
Search strategy
A systematic electronic and manual search covering the
period between 1 January1989 and 31 December 2007
was conducted to search for studies dealing with the
possible association between PD and cardiovascular dis-
eases. Published and unpublished articles were searched
to make the analysis as exhaustive as possible. Seven
databases were used: Medline via Pubmed, Pascal, Biosis
and Embase via Ovid, Lilacs, the Cochrane Library and
the French Public Health Database. Keywords were used
with boolean operators “OR” and “AND” combining
periodontal terms with cardiovascular ones in medical
subject headings (MeSH) or text words: [“periodontal
diseases” OR “periodontitis” OR “periodontal”] AND
generic terms [“cardiovascular diseases” OR “cardiovas-
cular”], and the more specific terms [“infarction” OR
“hypertension” OR “cardiopathy” OR “atherosclerosis”
OR “transient ischemic stroke” OR “peripheral artery
disease” OR “acute coronary syndrome” OR “angina”
OR “myocardial infarction” OR “ischemic cardiomy-
opathy”]. We also searched articles from the Google
search engine with the above keywords. No restriction
on language or type of article was applied. The bibli-
ographies of the articles found were reviewed to add
missing references. To detect unpublished studies, we
wrote to authors who had published more than two
studies in this field of research. Headings and abstracts
were scanned to select only clinical research reports
which dealt with cardiovascular diseases and PD, i.e.
to filter out articles concerning in vitro or genetic stud-
ies and other systemic diseases. Selected articles were
blinded with regard to title, authors and the journal in
which they were published.
Study selection criteria
Two reviewers independently screened full-text articles
to find inclusion criteria. To be included in this meta-
analysis studies had to:
• Be original epidemiological studies: when several
International Dental Journal (2009) Vol. 59/No.4
studies had been published from the same recruit-
ment, only the study with the largest number of
subjects was included
• Be observational studies: cross-sectional, case-con-
trol or cohort studies
• Concern living human subjects for the assessment
of periodontitis exposure
• Have an outcome related to cardiovascular diseases
as confirmed by coronary artery disease, or angina
pectoris, or acute myocardial infarction, or mortality
caused by cardiac pathology
• Have clinical exposure measurements related to PD
(pocket depth, clinical attachment loss, radiographic
bone loss, bleeding on probing, number of teeth,
Clinical Periodontal Sum Score, Periodontal Severity
Index or Oral Health Score)
• Be published between 1 January 1989 and 31 De-
cember 2007
• Correlate exposure and outcome by odds ratio (OR)
for cross-sectional and case-control studies, or rela-
tive risk (RR) for cohort studies. If these correla-
tions were absent, data had to be provided for their
calculation.
To permit data analysis, studies with continuous data
(OR or RR per unit increase) were excluded. Disagree-
ments between reviewers were resolved by discussion.
Methodological process
Results of cross sectional, case-control and cohort
studies could not be combined in our work because of
the high prevalence of cardiovascular diseases, which
gave a different estimation of risk. For this reason, two
separate analyses were conducted:
• One concerning cross-sectional and case-control
studies which could be combined from a statistical
point of view
• One concerning morbidity or/and mortality as out-
come in the cohort studies.
Data extraction
Two blinded dentists with postgraduate training in epi-
demiology and biostatistics (A.B. and S.N.) independ-
ently reviewed all the eligible studies using a standard
protocol and extracted information about study method,
population characteristics, exposure, outcome or end
point, adjusting factors and OR or RR data. When nec-
essary, authors were asked for additional data by email.
Discrepancies were cleared up by consensus.
Quality assessment
The quality of articles was assessed by two blinded and
calibrated examiners. Three checklists: the Université

Paul Sabatier18, Sign19,20 and Cho21 checklists permitted
the methodological validity and ethical values of the
included articles to be evaluated. The measure of agree-
ment between the raters was estimated by the kappa
coefficient. Any difference in evaluation was solved
by agreement between the two researchers. Articles
were classified in 4 levels with regard to various quality
criteria:
• Level A: attributed to articles validating internal,
external (objective of the study, criteria for the
selection of the sample population, definition of
exposure and outcomes clearly reported) and ethical
qualities
• Level B: for articles validating internal quality and
one of the two others
• Level C: for articles validating only internal quality
• Level D: for articles failing to validate internal quality
(several important methodological limitations, includ-
ing inadequate mode of allocation, biases in outcome
assessment, lack of appropriate follow-up and insuf-
ficient details reported for statistical analysis).
Statistical analysis
The same statistical procedures for cross-sectional, case-
control and cohort studies were applied. The OR and
RR were transformed to their logarithms so that the as-
sociated 95% confidence intervals, symmetric about the
relevant estimate, could be calculated22. Heterogeneity
among studies was tested by Cochran’s Q test. We quan-
tified statistical heterogeneity across studies by using the
I2 index25. In case of severe statistical heterogeneity (I2
>50%), sensitivity analysis to detect influential studies
allowed the study most responsible for it to be deleted.
This process was repeated until moderate heterogene-
ity with I2 index ≤50% was reached. Then, definitive
pooled OR or RR could be calculated and interpreted. In
the presence of a remaining significant variation across
studies, a random effects model was used to calculate
the overall OR or RR and the corresponding 95% con-
fidence intervals. Random effects estimate was based
on the DerSimonian-Laird method23,24. Otherwise, data
were combined to estimate the pooled OR or RR with
confidence intervals at 95% using the inverse variance
method. We tested for potential publication bias using
Begg’s24 test.
Subgroup analyses were performed to work out
whether particular characteristics of studies (geographic
origin of participants, PD criteria and cardiovascular
disease outcome) were related to the value of the
overall OR or RR. With the same purpose, univariate
meta-regression was used for the continuous variables
to test whether participants’ mean age and the study
quality score affected the final summary result. Statisti-
cal significance was fixed at 5%, except for Cochran’s Q
test, tests of publication bias, and tests of heterogeneity
199
across studies, where the α value was fixed at 10%. All
statistical analyses were performed using R software
version 2.2.0.
Result
Identification of studies
A total of 1,413 references (Figure 1) were identified by
keyword search from the seven databases. The identi-
fied articles were retrieved and the abstracts screened to
select only epidemiological studies with periodontal ex-
posure and cardiac outcome as mentioned. This resulted
in 218 studies. Then integral texts of the selected stud-
ies were reviewed to keep only original observational
studies without missing data. This revealed 47 studies.
Among these, 15 were excluded for data presentation
that did not allow pooling (missing summarised data, or
results not presented as ORs or RRs with 95% CI, or
ORs or RRs not calculable). Thus we identified 32 origi-
nal papers for inclusion in meta-analyses. Begg’s tests
failed to show significant bias for either meta-analysis
(Pcross-sectional / case control =0.59, Pcohort =0.45).
Study characteristics
Twenty-five cross-sectional or case-control studies were
considered in the analysis (Table 1)14, 26-49, and seven
cohort studies (Table 2)50-56; 11 of the 32 studies were
conducted among Scandinavian populations, eight con-
cerned North America, eight Europe, four South Amer-
ica, and one China. Although participation between men
and women was almost identical in cross-sectional and
case control studies (53% to 47%), more women (58%)
were engaged in cohort studies. Mean ages were close in
both types of studies, with a baseline mean age of 59.3
years for cross-sectional and case control studies and 52
years for cohorts. From the seven cohort studies, one
provided the results from men and women separately53,
another gave results for non fatal cardiovascular events
and fatal cardiovascular events separately56, and another
study separated non-fatal cardiovascular events and fatal
cardiovascular events, for men and women, resulting in
four different values of RRs54. Thus the total number
of results available for pooling in the meta-analysis of
cohort studies was 12.
Quality assessment
Kappa values calculated between the two evaluators
were very good (0.92, 0.93 and 0.94 for SIGN, Cho and
UPS checklists respectively). Overall quality for cross-
sectional and case-control studies was heterogeneous,
with 8 studies in level A, 7 in level B, 1 in level C and
9 in level D. Cohort studies were more homogeneous,
with 3 studies in level B and 4 in level C.
Blaizot et al.: Periodontal diseases and cardiovascular events
200

Figure 1. Flow diagram

International Dental Journal (2009) Vol. 59/No.4

 201

Table 1. Characteristics of the cross-sectional and case control studies included

Study Population Method Exposure Outcome Adjusting factors OR [CI 95%]

- Average age - Database N° Inclusion

- Age category - Country Subjects Period
- Characteristics

CROSS SECTIONAL STUDIES

Loesche et al. [42] - 68.5 - Veterans 320 NS NT 1-14 CHD (C) NS 2.64
- NS - USA [1.26-5.56]

Arbes et al.[27] - 54.1 - NHANES III 4850 1996 CAL ≥ 3mm in > AMI (Q) Age 3.77
- ≥ 40 - USA 67% of sites Sex [1.46-9.74]
Race
Smoking Status
Diabetes
Blood pressure
BMI

Katz et al. [40] - 39 - Israel 191 NS PPD CHD (C) Age 5.14
- 26- 53 - Army Servicemen Diabetes [1.37-19.28]
Hypertension
Hyperlipidemia
CAD

Buhlin et al. [14] - NC - LINDA 1577 NS PD (Q) CVD (C) Age 1.08
- 41-84 - Sweden Gender [0.78-1.51]]
Smoking
Income level
Civil status
Education

Malthaner et al. [43] - 63.2 - USA 100 NS Mean CAL ≥ CHD Age 1.635
- ≥ 40 - Military personnel & 3.5mm Smoking [0.46-5.75]
their families
No diabetes
No smoking history

Buhlin et al. [31] - NC - Sweden 638 NS PD (Q) CVD (C) Age 1.16
- 20-84 Gender [0.69-1.93]
Smoking
Diabetes
Education

Frisk et al. [35] - 64.7 - Sweden 1056 1992-93 TL >16 Angina pectoris Age 2.70
- NS - Female AMI Smoking [1.49-4.87]
Diabetes
Hypertension
Serum cholesterol
Serum Triglycerides
BMI
Alcohol
Life situation
Marital status

Nicolosi et al. [45] - 70 - Argentina 1999-2001 PPD >3mm in at Ischemic Age 2.04
- NS 341 least 1 site cardiopathy Gender [1.23-3.38]
Smoking
Diabetes
Hypertension
Hypercholesterolemia
Obesity

Table 1. Continued overleaf ...

Blaizot et al.: Periodontal diseases and cardiovascular events
 202

Table 1. Continued ...

Study Population Method Exposure Outcome Adjusting factors OR [CI 95%]

- Average age - Database N° Inclusion

- Age category - Country Subjects Period
- Characteristics

Elter et al. [34] - NC - ARIC 6744 NS CAL ≥ 6mm in ≥ CHD (C) Smoking 1.50
- 45-64 - USA 10% sites and Diabetes [1.10- 2.00]
TL≤16 Hypertension
HDL / LDL
Triglycerides
BMI
Current dentist

Holmlund et al. [39] - 53 - Sweden 902 NS PDSI >2.9 AMI Age 2.69
- 40-60 Gender [1.12-6.46]
Smoking

Gotsman et al. [38] - 58.27 - Israel 201 2001-2002 CAL≥5 CHD (C) Smoking 1.03
- 35-88 - Hadassah Hebrew Diabetes [1.01-1.04]
University Medical CHD family history
Center

CASE CONTROL STUDIES

Rutger Persson et - 62.6 - Sweden NS ABL ≥ 40% AMI (C) Smoking

al. [49] - 61-64 (±9) - No PD T 2months 80/ Non-smoking 14.1
before 80 Quit smoking [5.8-34.4]
No history of cardiac
problem

Geerts et al. [36] - 58.6 - Belgium 108/ 62 NS PPD ≥ 5mm in AMI (C) Age 6.5
- 57.7- 59.2 (± - No PD T ≥1pocket Angina pectoris Gender [1.8-23]
9-11) (C) Smoking
Diabetes
Hypertension
Hyperlipidemia
Diet
Alcohol consumption

Montebugnoli et al. - 53.3 - Italy 63/ 50 NS CPSS CHD (C) Age 4.61
[44] - 40-65 - Male Smoking [1.00-23.20]
Diabetes
Hypertension
HDL/LDL
CRP
Leukocytes
BMI
Social class

Renvert et al. [48] - 62.7 - Sweden 80/ 80 NS PPD AMI (C) Smoking 7.67
-NS - Age, gender & [1.13-51.92]
social matched

Coelho et al. [32] - NC - Brazil NS NT ≥ 4 in ≥ 1 site AMI (C) Age 4.03

- ≥ 20 21/ and PPD ≥ 4 mm Angina pectoris Gender [0.42-32.43]
128 or CAL ≥ 3mm (C) Smoking
Civilian Status

Table 1. Continued overleaf ...

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 203

Table 1. Continued ...

Study Population Method Exposure Outcome Adjusting factors OR [CI 95%]

- Average age - Database N° Inclusion

- Age category - Country Subjects Period
- Characteristics

Buhlin et al. [30] - 66.5 - Sweden 143/ NS PPD CHD (C) Age 3.8
-55-75 - Women 50 Smoking [1.68-8.74]
Diabetes
BMI
Education
Place of birth

Cueto et al. [33] - 60.4 - Spain 72/ NS CAL >3mm in AMI (C) Age 3.31
- 40- 75 - NT ≥ 1 77 > 33% of sites Gender [1.42-7.71]
PD T < 1year Diabetes
No ATB < 2 days Hypertension
Cholesterol
Exercise

Andriankaja et al. - 54.8 - USA 537/ NS Third tertile of AMI (C) Age
[26] - 35-69 - No history of car- 800 sites with CAL Gender 2.24
diac/cancer diseases ≥3mm and PPD Total pack-year [1.6-3.13]
NT ≥ 6 ≥ 4mm smoking
Diabetes
Hypertension
Cholesterol

Briggs et al. [29] - 57.4 - North Ireland 92/ NS Poor periodontal 50% narrowing Smoking 3.06
- ≥ 40 - Male 79 status of at least one Academic level [1.02-9.17]
No Diabetes coronary artery Alcohol
No ATB < 5months Maintain body weight
No PD T Exercise
No rheumatic or Unemployment
congenital heart Hobby
disease Plaque
CRP

Geismar et al.[37] - 63.6 - Denmark 2002 ABL > 4mm CHD (C) Gender 2.0
- NS 110/ Smoking [0.77-5.08
140 Diabetes
School attendance

Rech et al. [47] - 59.3 - Brazil 58/ 2002 PPD AMI (C) Age >60 4.5
- NS - Cases : hospital 57 Diabetes [1.30-15.60]
Gender matched Smoking

Latronico et al. [41] - 56.2 - Italy 15/ 2002-2004 CAL ≥3.5 mm AMI (C) NS 5.85
- 45-75 - Controls : same 19 Angina pectoris [1.033-
geographic area (C) 33.115]

Barilli et al. [28] -49.2 - Brazil 40/ NS Treatment CHD (C) NS 61

30-79 - ≥20 teeth 59 required for PPD [17.26-
≥6mm 214.86]

Nonnemacher et - 63.6 - Germany 45/ 2000- CAL>3 mm CHD (C ) Smoking 3.2

al. [46] - 48-80 - Men 45 2003 BMI [1.2-9.0]
No former smoker
Age matched

Blaizot et al.: Periodontal diseases and cardiovascular events

 204

Table 2. Characteristics of the cohort studies included

Study Population Method Exposure Endpoint Adjusting factors RR [CI
95%]
- Average age at - Database N° Study - Outcome
inclusion - Country Subjects duration - N° of cases
- Age category - Characteristics

DeStefano et al. - 61 - NHANES I 1786 1971 PD (C) - CHD MB Age 1.29

[50] - 25-74 - USA 1987 and CHD MT Gender [0.87-1.70]
- NS Race
Smoking
Diabetes
Cholesterol
SBP
BMI
Education
Poverty index
Marital status
Alcohol
Physical activity

Morrison et al. - NC - Canadian 9331 19701993 PD (C) - CHD MT Age 1.37

[51] - 35-84 Survey - 63 Gender [0.80-2.35]
Canada Smoking
Hypertension
Diabetes
Cholesterol
Province of resi-
dence

Jansson et al. [52] - 38.7 - Sweden 1001 19711996 Oral health - CHD MT Age 1.5
- 18-65 Score Plaque Gender [1.04-2.14]
index - 162 Smoking
CVD in 1970

Tuominen et al. - 46.7 - Finland 4910 19781990 PPD ≥ 4mm - CHD MT Age ♂ 1.0
[53] - ≥ 30 - ♂ 229 Smoking [0.6-1.6]
♂ 2518 ♀ 90 Diabetes
Hypertension Hy- ♀ 1.5
♀ 2392 percholesterolemia [0.6-3.8]
Education

NT - CHD MB
- 53.6 - Health Profes- 19861998 - 1654 MB 1.36
- 40-75 sionals 41407 [1.11-1.67]
- USA Age
- Men Smoking MT 1.79
Diabetes [1.34-2.40]
Hypertension Hy-
Hung et al. [54] 19921998 - CHD MT percholesterolemia
- 57.9 - Nurses Health 58974 - 562 BMI MB 1.64
- 30-55 - USA Alcohol [1.31-2.05]
- Women Physical activity
MT 1.65
[1.11-2.46]

Abnet et al. [55] 28 790 19862001 TL greater - MT Age 1.28

- 52 - China than the loess Gender [1.17-1.40]
- NS smoothed age- - 1932 cases Ever smoked
specific median
TL at baseline

Cabrera et 1622 19681993 TL > 10 - AMI MB Socioeconomic MB 1.45

al. [56] - 50 - Sweden CVD MT status [1.14-1.83]
- 38-60 - Women Husband’s occupa-
- NS tional category MT 1.34
Education [1.05-1.71]
combined income

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Legends of tables 1 and 2
- ABL : Alveolar Bone Loss
- ATB : Antibiotherapy
- AMI : Acute Myocardial Infarction
- BMI : Body Mass Index
- CA : Coronary Angioplasty
- CAL : Clinical Attachment Loss
- CHD ( C ) : Coronary Heart Disease confirmed by cardiologist(s)
- CHD ( Q ) : Coronary Heart Disease established by questionnaire
- CPSS : Clinical Periodontal Sum Score
- CRP : C Reactive Protein
- CVD : Cardiovascular Disease
- HDL : High Density Protein
- LDL : Low Density Protein
- MB : Morbidity
- MT : Mortality
- N° : Number
- NC : Non Calculable
- NS : Not stated
- NT : Number of Teeth
- OR [CI 95 %] : Odds Ratio with 95% Confidence Interval
- PD ( C ) : Periodontitis confirmed by a dentist
- PD ( Q ) : Periodontitis established by questionnaire
- PDSI : Periodontal Severity Index
- PDT : Periodontal Treatment
- PPD : Periodontal Pocket Depth
- RR [CI 95 %] : Relative Risk with 95 % Confidence Interval
- RS : Revascularization Surgery
- SBP : Systolic Blood Pressure
Meta-analyses
Initial pooling of the 25 cross-sectional or case-control
studies revealed a severe statistical heterogeneity among
studies (Q=195.56, p<0.0001, I2=87.7%). The sensitiv-
ity analysis identified three sources of severe statistical
heterogeneity28,38,49. These references were then excluded
from the meta-analysis process and the reasons for the
heterogeneity were investigated. For two studies28,49, the
ORs used for pooling were extreme values (OR>10).
For one28, this could be explained by an inappropriate
report of data leading to an inadequate calculation of
the OR and for the other49 by the lack of accounting
for smoking status in the overall sample. For a further
study38, the statistical heterogeneity was induced by
the extreme narrowness of the confidence interval
(OR=1.03, 95% CI [1.01,1.04]), which could not be ex-
plained by particularly high power of the study (n=201).
The deletion of these references resulted in 22 studies
(Q=41.88, p=0.0044, I2 = 49.9%). As a significant vari-
ation remained across studies, a random effects model
was used to calculate the overall OR from case-control
and cross-sectional studies. This indicated that there
were higher odds of developing cardiovascular diseases
in patients with periodontal disease, with a significant
pooled OR of 2.35 [CI [1.87; 2.96], p< 0.0001, random
effect model].
None of the 12 results from the seven cohort stud-
ies induced severe statistical heterogeneity (Q=11.66,
p=0.39 and I2=5.6%), so the 12 results were combined
205
(Figure 1). The meta-analysis of cohort studies showed
that patients with periodontal disease had a significantly
(34%) increased risk of developing cardiovascular dis-
eases (pooled RR=1.34 [CI [1.27; 1.42], p< 0.0001, fixed
effect model]).
Figure 2 shows the forest plots with the OR or RR
and their 95% confidence interval. Although all the 34
results had OR or RR greater than or equal to 1.00, only
24 were significantly so.
Analysis of residual heterogeneity
Meta-regression and subgroup analyses resulted in non-
significant or borderline effects for mean age (Pcross-sectional
/ case control
=0.11, Pcohort =0.06), study quality (Pcross-sectional /
case control
=0.64, Pcohort=0.09), periodontal evaluation cri-
teria (soft tissue assessment vs. loss of alveolar bone vs.
number of teeth Pcross-sectional / case control =0.90, Pcohort =0.12),
and cardiac outcome in cohort studies (mortality vs.
morbidity vs. mortality and morbidity, Pcohort =0.34).
In cross-sectional and case control studies, there
were some trends to suggest possible sources of het-
erogeneity due to the cardiac outcome used in the dif-
ferent studies (coronary heart disease OR=1.97 [1.49;
2.60], acute myocardial infarction OR=2.74 [2.16; 3.48];
p=0.08), and due to geographic area of origin (Europe
OR=3.95 [2.54 6.15], South America OR=2.34 [1.48;
3.70], North America OR=2.02 [1.49; 2.73], Scandina-
vian countries OR=2.00 [1.27; 3.15] ; p=0.08).
Finally, in cohort studies, it appeared that the value
of the global RR could be influenced by the geographic
area of origin of the population (North America
RR=1.50 [1.34; 1.68], Scandinavian countries RR=1.30
[1.17; 1.44], China RR=1.28 [1.17; 1.40]; p=0.08).
Discussion
Data analyses in this study show that subjects exposed
to PD had higher odds and a higher risk of develop-
ing cardiovascular diseases than subjects without PD.
Cross-sectional, case-control and cohort studies gave
significant and consistent results.
The results of these meta-analyses are slightly
higher than those published by Janket57 (RR 1.19; CI
[1.08-1.32]), who combined nine cohorts with both
cerebrovascular and cardiovascular diseases. Results of
another meta-analysis58 combining six cohort and two
cross-sectional studies are lower (RR 1.15; CI [1.06-
1.25]). The advantages of the present meta-analysis over
previous ones are, first, to study the impact of PD on
cardiovascular diseases specifically, without including
other peripheral vascular diseases and, second, to sepa-
rate cross-sectional studies from cohorts in the statistical
analyses since, because of the high prevalence of cardio-
vascular diseases, OR and RR cannot be combined.
Work focusing on coronary heart diseases has re-
cently been published59. It analyses cross sectional, case
Blaizot et al.: Periodontal diseases and cardiovascular events
206
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Figure 2. Forest plots of the cross-sectional, case control and cohort studies included

International Dental Journal (2009) Vol. 59/No.4


control and cohort studies (OR cross sectional=1.59; CI [1.33.
1.91], OR case control=2.22; CI [1.59; 3.12], RR cohort=1.24 CI
[1.14; 1.36] respectively). Although our results are simi-
lar, the originality of the present work is the particular
focus on heterogeneity analysis showing some evidence
for differences related to geographic areas and cardiac
outcomes. Scandinavian and American populations
seem to present a weaker association between PD and
coronary heart diseases than European ones.
Evidence Based Medicine suggests that randomised
controlled trials have the highest level of evidence to
establish causal relationships, but this type of research
cannot be used to answer all clinical questions for ethi-
cal, methodological or logistic reasons. In some situa-
tions, only well-designed epidemiological studies can be
conducted. Some criteria originally proposed by Hill and
discussed by Lilienfeld60 favour the causal relationship:
• Strength of association: the results of this meta-
analysis show significant association for both pooled
OR and pooled RR
• Consistency: all the studies give results equal to or
greater than 1.00 and 70% are significant. None
provided a value of OR or RR less than 1.00, a situa-
tion which would arise if cardiovascular disease were
more likely in those without PD than those with it
• Correct time sequence, which is underlined by cohort
studies where subjects were exposed to the risk fac-
tor, in this case PD, before developing cardiovascular
events. A problem to be pointed out is the long
period between the start of exposure to PD and
occurrence of a cardiac event.
• Dose effect relationship, i.e. the risk of developing a
cardiovascular event has to vary with the severity of
PD. This could not be assessed in the present meta-
analysis because of the lack of uniformity between
studies. This is a great limitation of the present work;
studies using per unit increase risk and subgroup
analyses (mild, moderate and severe periodontitis for
example) could not be pooled because of different
definitions of periodontal criteria.
• Biological plausibility, i.e. the epidemiological as-
sociation is supported by the combination of three
fundamental concepts that prove the biological
plausibility of PD as a risk factor for cardiovascular
diseases.
First, the infectious risk theory was put forward by
Haraszthy et al.7, who detected the periopathogens in
carotid endarectomy specimens. It is known that infec-
tious agents are implicated in the different stages of
atherosclerosis.
Second, by an inflammatory theory, it is now estab-
lished that inflammatory processes are implicated in
atherosclerosis but, nevertheless, it is not sure whether
this implication is part of the pathogenesis or just a
consequence of the disease61. For example, stimulation
of cytokines and C-reactive protein are correlated with
207
both PD and cardiovascular disease62.
The third concept is the immunological theory,
which has not yet been proved by direct clinical or ex-
perimental association but is suspected because of cer-
tain mechanisms, such as the activation of coagulating
factor IX by gingipains, a proteolytic system produced
by Porphyromonas gingivalis9.
It seems that theories explaining the causal associa-
tion are reasonable but need further clarification.
• The coherence of causal association between PD
and cardiovascular diseases implies that PD can be
implicated in other systemic diseases. PD has been
associated with pre-term birth, diabetes and respira-
tory infections63-65.
• Animal experimentation. Such experiments are pro-
posed to better understand the physiopathology of
periodontal and cardiovascular diseases. Although
they are hardly generalisable to humans, they remain
an essential step before human experimentation. For
example, Ebersole et al.66 have shown that C-reactive
protein and fibrinogen levels increase during the
progression of PD in primates.
Other experiments show that PD can accelerate the
progression of atherosclerosis at its different stages.
Studies have found that Platelet Aggregation-Associ-
ated Protein Streptococcus sangis and Porphyromonas gingivalis
interact with circulating platelets and may contribute to
the risk of acute thromboembolic events67-69.
• The analogy assumes that an association has a higher
causal relation if infections other than PD are capa-
ble of inducing the development and progression of
atherosclerotic plaque. For example, infection with
Chlamydia pneumonia and cytomegalovirus seem to be
associated with cardiovascular diseases70,71.
The major limitation of this review was the clinical
heterogeneity among the studies with regard to both
outcome and exposure definitions. Cardiovascular
diseases are a group of diseases that share the same
consequence, namely cardiac atherosclerosis. These
diseases are grouped under ischemic heart diseases
in the International Classification of Disease 10. Since the
meta-analysis methodology requires well defined, com-
mon outcome criteria, we restricted inclusion to studies
assessing ischemic heart diseases only. Moreover, we
performed subgroup analyses to distinguish between
morbidity and mortality in cohort studies, and between
coronary heart disease and acute myocardial infarction
in cross-sectional and case-control studies. Interestingly,
we found that periodontal disease was more associ-
ated with an acute cardiac event (i.e. acute myocardial
infarction) than with a chronic cardiac condition (i.e.
coronary heart disease). This paradoxical result needs
to be further investigated in future studies.
Blaizot et al.: Periodontal diseases and cardiovascular events
208
According to the American Association of Periodontology
1999, periodontal disease should be diagnosed by the
measure of clinical attachment loss. Other periodontal
outcomes such as pocket depth, number of teeth lost
for periodontal reasons, or even self-reported periodon-
titis might be useful in observational studies conducted
on large sample sizes. However, this variety of criteria
leads to difficulty in comparing studies, and to a need for
careful interpretation of meta-analyses results. Today,
the research community needs a strong consensus to
develop a standardised protocol to assess the periodon-
tal status of subjects included in studies. For the studies
conducted on the periodontal inflammation-systemic
disease interaction, a relevant way to determine the
severity of periodontal disease could be the estimation
of the periodontal inflamed surface area (PISA)72. In the
present analysis, we included all studies dealing with at
least one clinical criterion for diagnosis of periodontal
disease. Thus we excluded the studies which only used
biological, microbiological and/or genetic methods to
assess periodontal status. Moreover, subgroup analyses
were performed to detect any differential strengths of
association between cardiovascular and periodontal dis-
eases according to the different clinical criteria used for
periodontitis definition. We found no evidence of such
a differential effect between the included studies.
The epidemiological and physiopathological research
supports a causal relation between PD and cardiovascu-
lar diseases. But this association is not only causal, it has
to be considered as non-causal too. For example, certain
genetic or environmental confounding factors, such as
tobacco, increase the risk of PD and cardiovascular dis-
eases independently5. Further studies are therefore nec-
essary to illustrate the physio-pathological mechanisms
and take the confounding factors into account so as to
allow better planning of prevention programmes.
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Correspondence to: Dr M Sixou, Faculté de Chirurgie Dentaire, 3
chemin des maraîchers, 31062 Toulouse cedex 04, France. Email :
alessandra.blaizot@wanadoo.fr, jn.vergnes@free.fr
Blaizot et al.: Periodontal diseases and cardiovascular events