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Volume 8 Number 1 December 2003

Associations Between Periodontal Disease and Risk


for Atherosclerosis, Cardiovascular Disease, and Stroke.
A Systematic Review
Frank A. Scannapieco,* Renee B. Bush, and Susanna Paju*
* Department of Oral Biology, School of Dental Medicine, University at Buffalo, State University of New York, Buffalo, New York.
Health Sciences Library.

Background: Recent studies implicate exposure to systemic conditions involving chronic inflammation, including chronic periodontitis,
in the etiology of atherosclerosis.
Rationale: A systematic review of the literature was conducted to
assess the association between chronic inflammatory periodontal disease
and atherosclerosis.
Focused Question: Does periodontal disease influence the initiation/
progression of atherosclerosis and, therefore, cardiovascular disease
(CVD), stroke, and peripheral vascular disease (PVD)?
Search Protocol: MEDLINE, pre-MEDLINE, MEDLINE Daily Update,
and the Cochrane Controlled Trials Register were searched to identify
human studies that related variables associated with atherosclerosis to
periodontal disease. Searches were made for papers published from
1966 through March 2002.
Inclusion criteria: Published randomized controlled clinical trials
(RCTs), longitudinal, cohort, and case-control studies were included.
Study participants included those with atherosclerosis, myocardial infarction (MI), stroke, or PVD. Oral conditions included periodontal disease.
Exclusion criteria: Only studies on humans were included.
Data Collection and Analysis: Because the studies used different
oral assessment measures, it was not possible to perform a metaanalysis of the data reported. Weighted mean differences, relative
risks, or odds ratios were compared for cohort studies.
Main Results
1. Of the initial 1,526 studies identified, 31 (including 8 case-control
and 18 cross-sectional reports) were included in the analysis.
Taken together, most of the literature supports a modest association between periodontal disease and atherosclerosis. However,
data reported in several studies do not show this association.
2. The absence of a standard definition and measures for periodontal disease complicates interpretation of results, as do
potential confounding risk factors common to both conditions.
Reviewers Conclusions
1. Periodontal disease may be modestly associated with atherosclerosis, MI, and CVD.
2. Additional large-scale longitudinal epidemiologic and intervention
studies are necessary to validate this association and to determine causality.
Ann Periodontol 2003;8:38-53.
KEY WORDS
Atherosclerosis/etiology; inflammation; periodontal diseases/
complications; risk factors; literature review.
38

BACKGROUND
Etiology of Atherosclerosis,
Cardiovascular Disease,
and Stroke
The major contributing factor in the
majority of cases of cardiovascular
disease (CVD) and cerebrovascular
disease (stroke) is atherosclerosis.
One of the outcomes of this disease
process is the narrowing of the arteries resulting from subendothelial
deposition of cholesterol, cholesterol
esters, and calcium within the vessel
walls. These cholesterol-rich plaques
also contain a variety of cell types,
including fibroblasts and immune
cells.1 Rupture of the atherosclerotic
plaques yield thrombi that travel distally to occlude the artery, resulting
in myocardial infarction or stroke.
Several factors increase the risk
for atherosclerosis including a predisposition for elevated levels of cholesterol and triglyceride in the blood;
high blood pressure; diabetes; and
cigarette smoking.
Normal cells obtain most of the
cholesterol they need for normal
functioning by taking up cholesterol
from the blood through receptormediated endocytosis. Cholesterol
is transported in the blood bound
to low-density lipoproteins, or LDLs.
These LDLs bind to specific transmembrane receptor proteins for

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Scannapieco, Bush, Paju

transport into the cell. Cholesterol uptake is blocked


in some people (e.g., due to an apolipoprotein E
defect), and excess cholesterol accumulates in the
blood to eventually form atherosclerotic plaques. If
these plaques occlude blood flow in brain arteries, the
result can be stroke; if they occur in coronary arteries, it can lead to myocardial infarction.

sis,9,11,16-26 several epidemiologic studies have found


no such relationship.13,26-28
The goal of this systematic review was to identify
all literature pertinent to this issue, to critically evaluate
it and understand the current state of knowledge on this
subject, and to point out directions for additional
research.

Role of Inflammation in Atherosclerosis,


Cardiovascular Disease, and Stroke
A recent and growing literature implicates infection,
local and/or systemic inflammation, and possibly
autoimmunity in the pathogenesis of atherosclerosis.2
Arterial inflammation may be locally increased by lipid
imbalances, hemodynamic stress, and immune reactions directed against the vascular wall, eventually
leading to the formation of complicated atherosclerotic
lesions.3 This inflammation-mediated damage may initiate or contribute to the progression of the atherosclerotic plaque. A number of pathogens appear to be
associated with atherosclerotic plaques, and alterations
in the immune responsiveness may compromise clearance of the organism from these plaques. One of the
best studied of these associations involves Chlamydia
pneumoniae, a common intracellular bacterium that
causes pneumonia and milder respiratory tract infections. Recently, C. pneumoniae DNA and proteins have
been detected in arteries of patients with giant cell
arteritis,4 and in endarterectomy samples.5 Elevated
antibody levels against C. pneumoniae have been
measured in patients with coronary heart disease compared to controls.6
Serum inflammatory biomarkers such as C-reactive
protein (CRP) appear to be elevated in subjects with
atherosclerosis.7 Other suggested biomarkers include
fibrinogen, cell adhesion molecules, and various inflammatory cytokines.8 In fact, models using CRP together
with lipid profiles appear to predict risk for cardiovascular events better than the use of lipids alone.

FOCUSED QUESTION
We attempted to answer the following focused question,
Does periodontal disease influence the initiation/
progression of atherosclerosis (and therefore CVD,
stroke, and peripheral vascular disease)?

RATIONALE
The first suggestion that periodontal inflammation may
be related to atherosclerosis came in a paper published in 1988.9 These investigators compared the oral
health (measured by the Community Periodontal Index
of Treatment Needs) of 211 male patients in Yugoslavia
who experienced an MI with 336 control patients. They
noted that the MI group had worse periodontal health
than did the control group. Subsequent case-control
studies also showed a relationship of poor oral health
to MI.10-13 In addition, risk indicators for cardiovascular
disease have also been shown to be elevated in subjects with periodontitis.14,15 There has been an everincreasing literature in response to this notion. Although
the majority of publications have suggested an association between poor oral health and atherosclero-

SEARCH PROTOCOL
Data Sources and Search Strategy
The search strategy was defined to include randomized
controlled clinical trials (RCTS), longitudinal, cohort,
and case-control studies.
Search terms: Searches were run by one of the
reviewers (RB) using Ovid Search software of MEDLINE (1966-March 2002), MEDLINE Daily Update, and
Cochrane Controlled Trials Register (CCTR) updated
to first quarter of 2002. MEDLINE and MEDLINE Daily
Update were searched using medical subject headings
(MeSH terms). Reference lists of previously published
review articles were also searched. All MeSH terms
employed were exploded to expand retrieval to those
records that were assigned the more narrow related
MeSH term. The CCTR database and Pre-MEDLINE
required use of keywords (we used both American and
British spellings). All searches included the term and
human.
MeSH terms: Cardiovascular diseases, or heart diseases, or arteriosclerosis, or cerebrovascular disorders,
or carotid artery diseases, or peripheral vascular diseases, or cerebrovascular accident, or hypercholesterolemia.
Oral conditions: Periodontal diseases, tooth diseases,
or dental plaque index.
Key words: Arteriosclerosis, or atherosclerosis, or
carotid artery disease, or myocardial infarction, or
coronary disease, or cardiovascular disease, or peripheral vascular disease, or hypercholesterolemia, or
hypercholesterolaemia, or cerebrovascular disorder, or
cerebrovascular accident.
Oral conditions: Periodontal disease, or periodontitis,
or periodontal attachment loss, or alveolar bone loss,
or dental plaque, or oral hygiene.
Inclusion criteria: The reports included in the review
were those that recruited participants with atherosclerosis, myocardial infarction (MI), stroke, or peripheral
vascular disease. Oral conditions considered included
periodontal disease (as measured by assessments of
gingival inflammation, probing depth, clinical attachment loss, and/or radiographic bone loss). Our search
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Periodontal Disease and Risk for Atherosclerosis, Cardiovascular Disease, and Stroke

strategy also considered studies that tested the effect


of periodontal intervention on the initiation and progression of atherosclerosis, MI, stroke, or peripheral
vascular disease.
Exclusion criteria: The search was limited only to
studies of humans.
Outcomes: The following outcome measures were
assessed:
1. Primary outcome: increased incidence of MI or
stroke associated with periodontal disease.
2. Secondary outcomes: deficient measures of heart
function or surrogates of cardiovascular risk, such as
measures of endothelial function, intima-media wall thickness, vascular calcification, blood lipids, or C-reactive
protein levels associated with periodontal disease.
3. Patient-centered outcomes: quality of life issues.
4. Adverse outcomes: intraoral adverse effects,
increased rate of MI, stroke.
Data Collection and Analysis
Titles and abstracts of articles obtained using the above
described search strategy were screened by two independent readers (FAS and SP) and checked for agreement. The full text of the articles judged by title and
abstract to be relevant (by either FAS or SP) were read
and independently assessed against the stated inclusion
criteria.
For cohort studies that measured differences in rates
of disease between the group with oral disease and
the group without oral disease, weighted mean differences, relative risks or odds ratios were compared. No
published randomized controlled clinical trials evaluating primary outcomes were identified during the
course of this search.
Because of the heterogeneity in study design, methods of outcome measures, and target populations, no
effort was made to perform a meta-analysis of the
included studies.
Ranking of Studies
Included papers were graded according to previously
reported classifications.29,30
1. Systematic review of randomized controlled clinical
trials. RCTs with narrow confidence intervals.
2. Randomized controlled clinical trial. Low quality
systematic review.
3. Case-control study. Systematic review of case-control
studies.
4. Cross-sectional study.
RESULTS AND DISCUSSION
Following the described search strategy, MEDLINE
searching yielded 1,502 articles (1,020 in the English
language). In addition, 1 article was retrieved from the
MEDLINE Daily Update, 19 from the Pre-MEDLINE
and 4 from CCTR. Titles and abstracts were read and
the full text of all articles deemed relevant were
40

Volume 8 Number 1 December 2003

obtained and reviewed. This process resulted in the


selection of 31 articles that attempted to evaluate the
association of periodontal disease to CVD, stroke, or
peripheral vascular disease (Tables 1, 2, 3, and 4).
Search of the CCTR database revealed no articles of
relevance to the objectives of this review.
Interest in a possible connection between poor oral
health and atherosclerosis-induced heart disease began
with case and case-control studies in the 1980s. Since
then 4 additional case-control studies have been published. Of the 5 case-control studies (Table 1), 4
reported a positive association between indicators of
poor dental health and outcomes of atherosclerosis
(CVD).9-11,16 The one study reporting the absence of a
positive association was of very elderly subjects.13 Taken
together, these studies support a positive association
between the poor oral health and the prevalence of cardiovascular events. In some cases, the evidence points
to an association with periodontal disease.
Stimulated by these first case-control studies, 15
cross-sectional studies have since been published
(Table 2).17-28,31-33 Of these, 11 studies support a
modest association of periodontal disease with CVD,
after controlling for other cardiovascular risk factors,
particularly smoking. Because few studies use the
same oral assessment measures, it is not possible to
perform a valid meta-analysis by combining data from
these studies. Most studies were retrospective in design.
To date, results from a prospective, longitudinal epidemiologic study have not been reported.
In addition, 4 other studies have shown a positive
association between periodontal disease and
stroke,20,34-36 and another study has associated periodontal disease with peripheral vascular disease37
(Table 3).
In addition to the aforementioned epidemiologic studies, several other studies14,15,38-41 have reported an
association of periodontal disease with various parameters causally linked with the pathogenesis of atherosclerosis-induced disease (Table 4). These studies
demonstrate elevated levels of C-reactive protein, fibrinogen, white blood cells, cholesterol, and cytokines
in association with periodontal disease. Results of such
studies suggest possible mechanisms that link periodontal disease to the etiology of atherosclerosis.
One of the limitations of this analysis is the recognition of the great heterogeneity between studies in
assessment of oral disease, making comparision of
results difficult. An internationally accepted and standardized protocol for the assessment of oral health is
lacking. Limiting consideration only to studies that
used clinical attachment levels as a measure of periodontal disease history (a commonly accepted measure of periodontal damage) reveals general consensus
of a positive association between the extent of attachment loss and CVD.12-15

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Table 1.

Case-Control Studies Relating Oral Health to Cardiovascular Disease


Reference

Study Population

Oral Assessment

Cardiovascular
Assessment

Conclusions

Study
Ranking

Simonka et al.9
1988

Cases: 211 males with


previous heart attack.
Controls: 336 agematched patients
without heart attack.

KEP index
(= DMF: caries,
missing, and
filled teeth),
CPITN index.

Previously
diagnosed MI

Significant difference in CPITN


and demand for periodontal
surgery in patients >50 years
old with heart attack.
No difference in DMF
between cases and controls.

Mattila et al.10
1989

Cases: 40 males 50
years old; 60 males
and females <65
Controls: 102 ageand gender-matched.

Dental Severity Index


(sum of scores for
caries, periodontal
disease, periapical
pathosis and
pericoronitis).

Evidence of MI from
EKG and elevated
enzyme levels
(creatinine
phosphokinase
isoenzyme MB).

Dental health significantly


worse in patients with
acute MI than controls
after adjustment for
social class, smoking,
serum lipids, and diabetes.

Mattila et al.11
1993

100 subjects with


previous CVD.
No controls

Sum of the number


of vertical bone defects,
periapical lesions, caries,
pericoronitis, and
furcation lesions.

Extent of coronary
artery occlusion
by angiography.

Significant association
between dental infections
and severe coronary
atheromatosis in males.
No association in females.

Mattila et al.13
2000

Cases: 85 males and


females with proven
cardiovascular disease.
Controls: 53 age- and
gender-matched.

Indices based on sum


scores from periodontal
probing, furcation lesions;
radiographic examination
enumerating number of
carious teeth, impacted
teeth, periapical lesions,
vertical bone defects
and furcation lesions.

Subjects with
diagnosed
clinically or
angiographically
proven MI.

Dental indices (clinical


and radiographic) higher,
but not significant, among
CHD than controls.

Emingil et al.16
2000

Cases: 60 subjects
with acute MI (AMI).
Controls: 60 with
chronic coronary
heart disease
(CCHD).

Missing teeth,
restorations,
PD and BOP.

AMI subjects were


admitted to the
hospital for
treatment of AMI,
verified by EKG
and serum
enzyme levels.The
CCHD subjects
had history of MI
but not of
recent AMI.

Logistic regression
analysis showed % of
sites with BOP, N of
sites with PD 4,
number of restorations,
smoking status, and
triglyceride levels
were significantly
increased in AMI subjects
(P <0.05).These results
suggest that periodontal
disease may be associated
with acute MI.

It has been suggested that the association observed


between atherosclerosis-induced disease and periodontal disease is due to etiologic factors common to
both disease processes, such as lifestyle practices like
cigarette smoking.20,21,24 Thus, dissection of the independent role of lifestyle factors from the effect of periodontal inflammation on atherosclerosis will require
conducting of large longitudinal epidemiologic studies
of never smokers in addition to large randomized
controlled clinical trials of periodontal intervention to

prevent the initiation and progression of atherosclerosis-induced diseases.


REVIEWERS CONCLUSIONS
Periodontal disease appears to be moderately associated with atherosclerosis-induced diseases such as
coronary artery disease, stroke and peripheral vascular
disease. The extent to which the initiation and/or progression of atherosclerosis is influenced by periodontal infection or inflammation is presently unknown.
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Table 2.

Cross-Sectional and Longitudinal Studies


Reference

42

Study Population

Oral Assessment

DeStefano et al.17 1993

9,760 subjects enrolled in the


National Health and Nutrition Survey
(NHANES) I from 1971 to
1974. Follow-up until 1982.

N decayed permanent teeth. Periodontal


classification (no disease; gingivitis; periodontitis
with >4 mm pockets; no teeth). Periodontal
index. Oral hygiene index).

Paunio et al.18 1993

1,384 Finnish males; 868 re-examined.

N missing teeth.

Joshipura et al.19 1996

44,119 participants of the Health


Professionals Follow-up Study
(58% were dentists).

Self-reported number of teeth,


and history of periodontal disease

Beck et al.20 1996

203 cases; 940 controls from VA


Dental Longitudinal Study component
of the Normative Aging Study.

Alveolar bone loss measured from


radiographs measured using Schei ruler;
worst probing depth per tooth.

Loesche et al.21 1998

320 veterans >60 years old.

Number of teeth (0-14 or 15-28 );


probing depths, attachment level and
gingival recession; plaque index; gingival
bleeding. Plaque N-benzoyl-DL-arginine-2naphthylamide enzyme score; complaint
of xerostomia.

Arbes et al.22 1999

5,564 subjects >40 years old.

% attachment loss of all teeth


3 mm (categorized as 4 levels).

Morrison et al.23 1999

10,368 subjects enrolled in


Nutrition Canada Survey.

Periodontal disease classified as none,


mild gingivitis, severe gingivitis,
obvious pockets, loose
teeth, and edentulous.

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Table 2. (continued)

Cross-Sectional and Longitudinal Studies


Cardiovascular Assessment

Major Findings or Odds Ratio


(OR) or Risk Ratio (RR) (95% CI)

Conclusions

Study Grade

Admission to hospital for


CHD treatment. Mortality
due to coronary heart disease.

RR 1.72 (1.10-2.68) when


periodontitis compared
to CHD.

Dental disease is associated with


a small increased risk of CHD.

Screening examination using


questionnaires and interviews
about previous disease; chest
X-rays, EKG, blood pressure.
Subjects with any suggestive finding
were re-examined with clinical
examination and diagnosis by
physician. CHD defined as
angina pectoris or previous MI.

Prevalence of ischemic heart


disease was correlated with the
number of missing teeth; around
10% when less than 1/2 teeth
lost and around 20% when at
least 1/2 teeth were lost.

A weak but statistically significant


association between missing
teeth and ischemic
heart disease.

Fatal/non-fatal MI, sudden death.


Subjects with revascularization
procedures excluded.

Men with periodontal disease and


with 0-10 teeth, as compared to
men with 25+ teeth, RR =
1.67 (1.03-2.71). No association
among men without periodontal
disease, RR = 1.11(0.74-1.68).

A small association between


tooth loss and CHD risk; no
overall association between
periodontal disease and CHD.

Total CHD determined as cases of


non-fatal MI, angina pectoris, and CHD
deaths. Stroke diagnosed by means
of history and physical examination.

Incidence odds ratios:


Bone loss and total CHD 1.5,
Bone loss and fatal CHD 1.9,
Bone loss and stroke 2.8.

Periodontal disease associated


with a moderate risk
of CHD/stroke.

Diagnosis of MI, bypass surgery,


clinical angina, EKG, serum enzyme
levels, angiography; positive response
to treatment for heart disease.

Significant association between CHD


and poor oral health in independent
living subjects. OR for 1-14 teeth
2.83 (1.11-7.2); for papillary gingival
bleeding score >1.5-4.6 (1.32-15.97);
for positive plaque BANA score
2.46 (1.13-5.38); for complaint of
xerostomia 2.6 (1.02-6.62). For
dependent living subjects: 1-14 teeth
6.16 (1.60-23.7); for complaint of
xerostomia 2.92 (1.02-8.39).

Several oral health variables


are risk indicators for CHD.

Self-reported MI.

Relative to 0% category, the unadjusted


odds of heart attack increased with
each higher category of attachment
loss (0-33%, 33-67%, 67+%) were
2.2 (1.3.-3.8), 5.5 (3.4-9.1) and
9.8 (4.5-21.0), respectively.When
adjusted for age, gender, race, etc.
OR was 1.38 (0.75-2.54),
2.28 (1.18-4.39), and 3.77 (1.46-9.74).

Results support an association


between periodontal disease
and coronary heart disease.

Death attributed to coronary


heart and cerebrovascular disease

The relation between dental health (severe gingivitis and edentulous status)
and the risk of fatal CHD and CVD
was (rate ratios-RR) 2.15 (1.25-3.72)
and 1.90 (1.17-3.10), respectively, as
adjusted for confounding variables.

These data indicate that


poor dental health is
associated with an
increased risk of
fatal CHD.

(continued)

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Volume 8 Number 1 December 2003

Table 2. (continued)

Cross-Sectional and Longitudinal Studies


Reference

44

Study Population

Oral Assessment

Beck et al.24 2001

6,017 persons from the


Atherosclerosis Risk in
Communities Study 1996.

Periodontitis was defined by extent


of attachment loss 3 mm: none/mild
(<10%), moderate (10% to <30%), or
severe (30%).

Jansson et al.25 2001

1,393 subjects from the County


of Stockholm admitted to the
study in 1979. A follow-up
was performed in 1997.

N missing teeth, apical lesions, and carious


lesions. Marginal bone loss (MBL) expressed as
% of the distance from apex to CEJ. MBL index
was defined as the mean of the MBL values
at all measurable points in an individual.

Hujoel et al.26 2000

8,032 dentate adults aged


25-74 years from NHANES-1
epidemiologic follow-up study.

Baseline periodontal status: periodontitis;


a periodontal pocket with attachment
loss; gingivitis, inflammation with no
attachment loss; periodontal health, no
attachment loss or inflammation.

Hujoel et al.27 2001

4,027 people who participated


in the NHANES-I.

Comparison of subjects with


periodontitis (pockets 4 mm
on any teeth) with edentulism.

Howell et al.28 2001

22,037 male subjects in


Physicians Health Study I.

Self-report of presence or absence


of periodontal disease at study entry.

Katz et al.31 2001

1,094 Israeli army servicemen aged


26-53 years (mean: 39 5);
151 had CHD.

Severity of periodontal disease


assessed by CPITN.

Takata et al.32 2001

697 octogenarians in Fukuoka


Prefecture, Japan.

Tooth loss and assessment of the


Community Periodontal Index.

Hujoel et al.33 2002

636 dentate individuals initially


enrolled in NHANES-1 who had
both medical and dental examinations,
reported a prior history of CVD, and
who were followed longitudinally.

Inclusion: History of prior CVD as


determined by a yes answer to 1 of
4 questions: Has a doctor ever told
you that you had a heart attack? Has
a doctor ever told you that you had a
stroke? Has a doctor ever told you
that you have heart failure? and During
the past 6 months have you used any
medicine, drugs, or pills for a weak heart? (continued)

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Table 2. (continued)

Cross-Sectional and Longitudinal Studies


Cardiovascular Assessment

Major Findings or Odds Ratio


(OR) or Risk Ratio (RR) (95% CI)

Conclusions

Study Ranking

Carotid artery intima-media


wall thickness (IMT) 1 mm.

Severe periodontitis (OR 1.31,


CI 1.03 -1.66) was associated
with IMT 1 mm, while adjusting
for the other factors.

Periodontitis may influence


atheroma formation.

Death due to CVD.

The sum of scores for number of


missing teeth, apical lesions, caries
lesions, and marginal bone loss was
significantly correlated to fatal coronary events in subjects 45 years old.

Poor dental health and smoking


are risk indicators of death
due to CVD.

Death from CHD or hospitalization


due to CHD, or revascularization
procedures, obtained from death
certificates and medical records.

Neither gingivitis nor periodontitis


was associated with a statistically
significant increased risk for CHD.

This study did not find


convincing evidence of a
causal association between
periodontal disease
and CHD risk.

Death from CHD, or hospitalization


due to CHD, or revascularization
procedures, obtained from death
certificates and medical records.

Confirmed elimination of
chronic dental infections (by
full-mouth dental extraction)
did not lead to a decreased risk
of experiencing a CHD event.

Reduction in periodontal
inflammation by
tooth extraction
will not prevent CHD.

A cardiovascular event was confirmed


after examination of all information
by an end points committee
blinded to participants periodontal
disease status. Nonfatal stroke was
defined as a typical neurologic deficit,
either sudden or rapid in onset,
that lasted >24 hours and was
attributed to a cerebrovascular event.
Cardiovascular death confirmed by
review of death certificates, hospital
records, and observers impressions.

No statistical association between


cardiovascular death or stroke and
self-reported periodontal disease
at baseline, compared to
those who did not.

Self-reported periodontal
disease is not an independent
predictor of subsequent
cardiovascular disease.

History of MI and/or anginal syndrome


with angiographic evidence of
significant coronary disease, or
suffer from atherosclerotic risk
factors; i.e., diabetes (fasting glucose).

A significant association between


CPITN score 4 and
hypercholesterolemia.

The generation of higher cholesterol blood levels is proposed


as a possible link between
chronic periodontal inflammation and atherosclerosis.

Abnormal ECG findings.

Individuals with <20 teeth had


increased prevalence of ST
depression and T-wave
abnormalities in ECG.

Tooth loss may be a predictor


of abnormal ECG findings
in the very elderly.

Periodontal disease was defined as: periodontitis: presence of 4 with pockets


and attachment loss, n = 236; gingivitis
n = 186; and periodontal health
n = 214. Individuals with gingivitis had
an overt area of inflammation which
may completely circumscribe the
tooth and which may have been
associated with pseudopockets.

No significant differences
observed between CHD
and periodontitis or gingivitis.

Periodontal disease does not


increase risk of CHD in
subjects with preexisting
heart disease.

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Table 3.

Studies Relating Human Oral Health to Stroke (Cerebrovascular Accident or CVA)


and Peripheral Vascular Disease
Reference

Study Population

Oral Assessment

Case-control study of 40 patients with ischemic


cerebral infarction under the age of 50, and
40 randomly selected community controls
matched for gender and age.

Total dental index that measured N carious lesions,


severity of periodontitis, N periapical lesions and
pericoronitis.The presence of subgingival calculus or
suppuration in the gingival pockets was measured.

Beck et al.20 1996

203 cases and 940 controls from VA Dental


Longitudinal Study component of the
Normative Aging Study.

Alveolar bone loss measured from radiographs


measured using Schei ruler; worst clinical PD
per tooth.

Loesche et al.35 1998

Cross-sectional study of 401 veterans


60 years of age.

N teeth (0-14 and 15-28 ); PD, attachment level, and


gingival recession; plaque index; gingival bleeding;
evaluation of salivary flow and xerostomia.

Wu et al.36 2000

9,962 participants enrolled in NHANES-I and


follow-up study.

Periodontal status was grouped into one of the


following: 1) no periodontal disease: no teeth with
periodontal disease, or 1 tooth with mild gingivitis
if 20 teeth; 2) gingivitis: 1 tooth with mild gingivitis or
a worse condition that did not fit category 1 or 3;
3) periodontitis: 4 or more teeth with overt pockets
or worse conditions; and 4) edentulousness (both
arches edentulous or all teeth were roots).

Mendez et al.37 1998

Assessment of a relationship between PVD


and periodontal disease by analyzing data
from the Normative Aging Study and Dental
Longitudinal Study of the US Department
of Veterans Affairs; 80 individuals with PVD
were compared with 1,030 control subjects.
Multivariate logistic regression analysis
was used.

Radiographic measures of alveolar bone loss estimated


from intraoral periapical films taken at baseline
using Schei ruler.

Syrjanen

et al.34

1989

Additional large-scale longitudinal epidemiologic and


interventional studies are necessary to validate this
association and to determine if the association is
causal.
Presently, insufficient evidence is available to justify
periodontal intervention to prevent the onset or progression of atherosclerosis-induced diseases.
FUTURE DIRECTIONS FOR RESEARCH
Studies to date provide equivocal evidence that periodontal disease has a causal link to atherosclerosis.
Further research must be conducted to definitively
establish the role of periodontal disease in the etiology
of athersclerosis. Randomized controlled clinical trials
that evaluate the effects of periodontal intervention
(that may include mechanical, chemical, or host mod46

ulatory approaches) in the prevention of atherosclerotic


disease as well as in the management of patients suffering the effects of atherosclerosis-induced diseases
(e.g., myocardial infarction, stroke) are necessary to
prove or disprove this link.
REFERENCES
1. Ross R. Cell biology of atherosclerosis. Annu Rev Physiol 1995;57:791-804.
2. Ross R. Atherosclerosis-An inflammatory disease. N Engl
J Med 1999;340:115-126.
3. Ludewig B, Zinkernagel RM, Hengartner H. Arterial
inflammation and atherosclerosis. Trends Cardiovasc
Med 2002;12:154-159.
4. Wagner AD, Gerard HC, Fresemann T, et al. Detection of
Chlamydia pneumoniae in giant cell vasculitis and correlation with the topographic arrangement of tissue-infiltrating
dendritic cells. Arthritis Rheum 2000;43:1543-1551.

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Table 3. (continued)

Studies Relating Human Oral Health to Stroke (Cerebrovascular Accident or CVA)


and Peripheral Vascular Disease
Stroke/PVD Assessment

Conclusions

Study Ranking

Diagnosis made by aorto-cervical angiography


or by detection of brain stem infarction or
cardiac emboli.

Poor oral health was more common in subjects with


ischemic cerebrovascular disease in patients <50 years
of age.

Stroke diagnosed by means of history and


physical examination.

Incidence OR for bone loss and stroke 2.8. Periodontal


disease associated with a moderate risk of CHD/stroke.

Diagnosis of stroke (CVA) determined from


hospital records, patient interview, CAT
scans, and physical and neurologic
examinations.

21% of the teeth in subjects with CVA had attachment


loss >6 mm compared to 12% in subjects without
CVA (P = 0.028). Dentate subjects with CVA had more
plaque and gingival bleeding than dentate subjects
without CVA.The presence of 15-28 teeth and
increased proportion of teeth with attachment loss
>6 mm were significantly related to CVA. Poor oral health
and dental neglect are associated with CVA.

Incident cases of CVA meeting at least 1 of


the following criteria: death certificate with
cause of death due to CVA or 1 or more
hospital/nursing home stays during the
follow-up period with discharge

Compared with no periodontal disease, the relative risks


(95% confidence intervals) for incident nonhemorrhagic
stroke were 1.24 (0.74-2.08) for gingivitis, 2.11 (1.30-3.42)
for periodontitis, and 1.41 (0.96-2.06) for edentulousness.

Subjects with periodontal disease at baseline


had a 2.27 increased risk of developing
PVD (95% CI 1.32-3.9, P = 0.003) after
excluding other vascular conditions from
the control group and excluding stroke
from the case group.

Periodontal disease emerged as a significant independent


risk factor for PVD in a multivariate analysis that
adjusted for other established risk factors.

5. Chiu B. Multiple infections in carotid atherosclerotic


plaques. Am Heart J 1999;138:S534-S536.
6. Saikku P, Leinonen M, Tenkanen L, et al. Chronic
Chlamydia pneumoniae infection as a risk factor for
coronary heart disease in the Helsinki Heart Study. Ann
Intern Med 1992;116:273-278.
7. Shah SH, Newby LK. C-reactive protein: A novel
marker of cardiovascular risk. Cardiol Rev 2003;11:
169-179.
8. Blake GJ, Ridker PM. Inflammatory bio-markers and
cardiovascular risk prediction. J Intern Med 2002;252:
283-294.
9. Simonka M, Skaleric U, Hojs D. Condition of teeth and
periodontal tissue in patients who had suffered a heart
attack (in Croatian). Zobozdrav Vestn 1988;43:81-83.
10. Mattila KJ, Nieminen MS, Valtonen VV, et al. Association
between dental health and acute myocardial infarction. Br
Med J 1989;298:779-782.

11. Mattila KJ, Valle MS, Nieminen MS, Valtonen VV, Hietaniemi
KL. Dental infections and coronary atherosclerosis. Atherosclerosis l993;103:205-211.
12. Mattila KJ, Valtonen VV, Nieminen M, Huttunen JK. Dental infection and the risk of new coronary events:
Prospective study of patients with documented coronary
artery disease. Clin Infect Dis 1995;20:588-592.
13. Mattila KJ, Asikainen S, Wolf J, Jousimies-Somer H,
Valtonen V, Nieminen M. Age, dental infections, and
coronary heart disease. J Dent Res 2000;79:756-760.
14. Loos BG, Craandijk J, Hoek FJ, Wertheim-van Dillen PME,
van der Velden U. Elevation of systemic markers related
to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 2000;71:1528-1534.
15. Ebersole JL, Machen RL, Steffen MJ, Willmann DE. Systemic acute-phase reactants, C-reactive protein and haptoglobin, in adult periodontitis. Clin Exp Immunol 1997;
107:347-352.
47

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Volume 8 Number 1 December 2003

Table 4.

Relationships of Markers of Atherosclerosis Associated with Human Periodontal Disease


Reference

48

Study Population

Outcome

Conclusions

Study
Ranking

Kweider et al.38
1993

Case control.
Cases: 50 consecutive patients
attending dental hospital.
Controls: 50 subjects with
healthy periodontium
recruited from hospital
patients and staff.

Dental indices (plaque index, gingival


index, CPITN) correlated significantly
with fibrinogen and WBC count (GI
and fibrinogen K = 3.17 and GI and
WBC K = 3.38).

Inflammatory dental disease


may influence fibrinogen
level and WBC count.

Ebersole et al.15
1997

40 subjects with periodontitis


(radiographic evidence of
bone loss, pockets >5 mm,
bleeding on probing) were
compared to 35 normal
subjects (who could exhibit
mild to moderate gingivitis
with pockets <4 mm).

C-reactive protein (CRP) and haptoglobin


(Hp) weresignificantly increased in
serum from periodontal patients
compared to healthy controls (P <0.05).

Localized periodontal
infections result in
increased inflammation
and tissue loss in the
periodontium and elicit
systemic host changes.

Wakai et al.39
1999

Cross-sectional
517 males and 113 females
23-83 years old.

Poor periodontal status (as measured


by CPITN) strongly associated with
high WBC count and CRP. Total
cholesterol and triglyceride not
associated with periodontal status.

Results suggest an
association between
periodontal status and
associated factors for
atherosclerosis.

Loos et al.14
2000

Case-control.
Cases: 107 consecutive
periodontal patients.
Controls: 43 subjects with
healthy periodontium.

Patients with periodontitis had higher


median CRP levels than periodontally
healthy controls (P = 0.030).
Subjects with periodontal disease
were more frequently seropositive
for interleukin 6, and plasma IL-6
levels were higher than in
periodontally healthy controls.

Periodontitis is associated
with higher levels of CRP,
IL-6, and neutrophils and
these inflammatory
factors potentially increase
the risk for cardiac events.

Wu et al.40
2000

10,146 subjects enrolled in


the Third National Health
and Nutrition Examination
Survey and its follow-up
study.

Significant associations between


indicators of poor periodontal health
status (gingival bleeding index, calculus
index, periodontal pocket depth,
attachment loss) and increased
CRP and fibrinogen.Weak or no
association between periodontal
status and total cholesterol or HDL.

CRP and fibrinogen are


possible intermediate
factors that may link
periodontal disease to
elevated cardiovascular
risk.

Noack et al.41
2001

Cross-sectional cohort study


of 174 subjects randomly
selected from a larger
cohort of 1,250 subjects.
59 subjects had moderate
periodontal attachment loss,
50 had severe attachment
loss and 65 periodontally
healthy subjects served
as controls.

Statistically significant increase in CRP in


subjects with periodontitis when
compared to healthy controls
(P = 0.036).

Positive correlation between


CRP and periodontal
status may be a pathway
in the association
periodontal disease
and CVD.

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16. Emingil G, Buduneli E, Aliyev A, Akilli A, Atilla G. Association between periodontal disease and acute myocardial infarction. J Periodontol 2000;71:1882-1886.
17. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russell
CM. Dental disease and risk of coronary heart disease
and mortality. Br Med J 1993;306:688-691.
18. Paunio K, Impivaara O, Tiekso J, Mki J. Missing teeth
and ischaemic heart disease in men aged 45-64 years.
Eur Heart J 1993;14(Suppl. K):54-56.
19. Joshipura KJ, Rimm EB, Douglass CW, Trichopoulos D,
Ascherio A, Willett WC. Poor oral health and coronary
heart disease. J Dent Res 1996;75:1631-1636.
20. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S.
Periodontal disease and cardiovascular disease. J Periodontol 1996;67:1123-1137.
21. Loesche WJ, Schork A, Terpenning MS, Chen YM,
Dominguez BL, Grossman N. Assessing the relationship
between dental disease and coronary heart disease in
elderly U.S. veterans. J Am Dent Assoc 1998;129:301-311.
22. Arbes SJ Jr, Slade GD, Beck JD. Association between
extent of periodontal attachment loss and self-reported
history of heart attack: An analysis of NHANES III data.
J Dent Res 1999;78:1777-1782.
23. Morrison HI, Ellison LF, Taylor GW. Periodontal disease
and risk of fatal coronary heart and cerebrovascular diseases. J Cardiovasc Risk 1999;6:7-11.
24. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM,
Offenbacher S. Relationship of periodontal disease to
carotid artery intima-media wall thickness: The Atherosclerosis Risk in Communities (ARIC) study. Arterioscler
Thromb Vasc Biol 2001;21:1816-1822.
25. Jansson L, Lavstedt S, Frithiof L, Theobald H. Relationship between oral health and mortality in cardiovascular diseases. J Clin Periodontol 2001;28:762-768.
26. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.
Periodontal disease and coronary heart disease risk.
JAMA 2000;284:1406-1410.
27. Hujoel PP, Drangsholt M, Spiekerman C, Derouen TA.
Examining the link between coronary heart disease and
the elimination of chronic dental infections. J Am Dent
Assoc 2001;132:883-889.
28. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Christen
WG. Periodontal disease and risk of subsequent cardiovascular disease in U.S. male physicians. J Am Coll Cardiol 2001;37:445-450.
29. Newman MG, Hujoel PP. Statement of purpose and methods. J Evid Based Dent Prac 2001;1:3A-5A.
30. Kahn KS, Riet GT, Popay J, Nixon J, Kleijnen J. Undertaking systematic reviews of research on effectiveness.
Phase 5. Study quality assessment. In: University of York
NHS Centre for Reviews and Dissemination; 2001. Available at: http://www.ac.uk/inst/crd/report4.htm. Accessed
March 2003.
31. Katz J, Chaushu G, Sharabi Y. On the association
between hypercholesterolemia, cardiovascular disease
and severe periodontal disease. J Clin Periodontol 2001;
28:865-868.
32. Takata Y, Ansai T, Matsumura K, et al. Relationship
between tooth loss and electrocardiographic abnormalities in octogenarians. J Dent Res 2001;80:1648-1652.
33. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.
Pre-existing cardiovascular disease and periodontitis: A
follow-up study. J Dent Res 2002;81:186-191.
34. Syrjnen J, Peltola J, Valtonen V, Iivanainen M, Kaste M,
Huttunen JK. Dental infections in association with cerebral infarction in young and middle-aged men. J Intern
Med 1989;225:179-184.

35. Loesche WJ, Schork A, Terpenning MS, Chen Y-M, Kerr C,


Dominguez BL. The relationship between dental disease
and cerebral vascular accident in elderly United States
veterans. Ann Periodontol 1998;3:161-174.
36. Wu T, Trevisan M, Genco RJ, Dorn JP, Falkner KL,
Sempos CT. Periodontal disease and risk of cerebrovascular disease. The First National Health and Nutrition
Examination Survey and its follow-up study. Arch Intern
Med 2000;160:2749-2755.
37. Mendez MV, Scott T, LaMorte W, Vokonas P, Menzoian
JO, Garcia R. An association between periodontal disease and peripheral vascular disease. Am J Surg 1998;
176:153-157.
38. Kweider M, Lowe GD, Murray GD, Kinane DF, McGowan
DA. Dental disease, fibrinogen and white cell count; links
with myocardial infarction? Scott Med J 1993;38:73-74.
39. Wakai K, Kawamura T, Umemura O, et al. Associations
of medical status and physical fitness with periodontal
disease. J Clin Periodontol 1999;26:664-672.
40. Wu T, Trevisan M, Genco RJ, Falkner KL, Dorn JP,
Sempos CT. Examination of the relation between periodontal health status and cardiovascular risk factors:
Serum total and high density lipoprotein cholesterol,
C-reactive protein, and plasma fibrinogen. Am J Epidemiol
2000;151:273-282.
41. Noack B, Genco RJ, Trevisan M, Grossi S, Zambon JJ,
De Nardin E. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol
2001;72:1221-1227.
Correspondence: Dr. Frank A. Scannapieco, Department of Oral
Biology, School of Dental Medicine, University at Buffalo,
State University of New York, 109 Foster Hall, Buffalo, NY 14214.
Fax: 716/829-3942; e-mail: fas1@ buffalo.edu.
Accepted for publication August 14, 2003.

APPENDIX A
CONSENSUS REPORT
Introduction
Both periodontal and cardiovascular diseases are relatively common, chronic, multifactorial conditions. The
concordant linkages or associations between these
coincident conditions may reflect chance occurrence,
the sharing of a common antecedent susceptibility or
resistance traits, common behaviors or exposures, or
the influence of one condition on the other. Furthermore, both conditions have heterogeneous clinical presentations and etiological and modifying components
may or may not be uniformly expressed clinically,
based upon the genetic background of the individual.
The initial observation that the prevalence of cardiovascular disease among chronic periodontitis patients
was higher than the general population was reported
over a decade ago suggesting that these two conditions
tend to cluster or self-aggregate within the population.1 Upon first consideration, it would appear that
these linkages of both periodontal disease and car49

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diovascular disease within subjects might easily be


explained by the presence of common behaviors or
traits that increase the risk for both conditions, such
as smoking or obesity. Thus, the challenge of any study
design and analytical experimental approach aimed at
quantifying the relative contribution of periodontal disease to cardiovascular disease is that the study needs
to include a wide range of additional risk factors or
markers that enable one to dissect out and quantify that
portion of the risk that is specifically attributable to
periodontal disease. That is, the effects of periodontal
disease need to be considered in the presence of full
measurements of other confounding or effect-modifying
variables, being as inclusive as possible. For this reason, studies must usually be fairly large and epidemiologic in nature, usually requiring at least 10 cases in
each subcell to adequately adjust or statistically correct for each possible risk factor that needs to be considered as a possible modifier of either periodontal
disease or cardiovascular disease. As a consequence
the initial analyses showed associations, which could
not be easily explained away by common risk factors,
that were based upon large heart studies or general
health studies that also had periodontal data.
It is important to note that in the consideration of
the available data the Section members and the reviewers were ever cognizant of the central importance of
examining for and evaluating the quality of the data
with regards to these critical issues of assessing the
potential contribution of confounders and covariates.
It is in this context that the evidence for an association between periodontal disease and systemic conditions, such as cardiovascular disease, pneumonia, and
adverse pregnancy outcomes has been uniformly and
systematically considered. Furthermore, it has now
been acknowledged that the manner in which periodontal disease is defined as a systemic exposure;
e.g., as a condition that may contribute risk for CVD,
may differ from traditional classifications of periodontal
disease. These traditional classifications use signs and
symptoms (such as bleeding scores) as an index of
exposure to quantify the risk for a tooth-related outcome, for example an increase in probing depth or
bone loss and not a systemic disease outcome. As yet
another example, bleeding sites and probing depths
may be a better reflection of systemic exposure than
attachment and bone loss, depending on the outcome
of interest.2 Thus, the definition of periodontal disease
which serves to define a periodontal case as a systematic exposure is a simplified, clinical measurement
representation of the triad of periodontal disease components: periodontal infection, inflammation, and clinical signs. For this reason, the diversity in the definitions
of periodontal case status that has been used to define
periodontal exposure among different studies is not a
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Volume 8 Number 1 December 2003

failure to recognize or apply traditional, uniform definitions, but rather is a data-driven reassessment of the
changing definitions or clustering of clinical signs that
best describe the relationships.
Despite these conceptual limitations that require a
paradigm shift in considering periodontal disease as
a possible etiologic contributor to cardiovascular
disease, the body of evidence continues to accrue
supporting a modest association even after thoughtful and complete statistical methodological correction
or adjustment for other risk factors, such as smoking.
However, residual confounding may still be present in
that these methods have not adequately captured the
appropriate measure of periodontal disease as an
exposure that increases the risk of a given systemic
disease or condition. But this is always a characteristic of epidemiologic, observational, and case-control
study designs. It is important to note that overcorrection for confounders can easily occur in these analytical approaches, as well. For example, the effects
of cholesterol on the risk for heart disease in large
data sets can be easily missed or nullified if non-relevant or non-exclusive variables are included in the
adjustments. These methodological issues, while
seemingly tangential to the current Consensus Report,
highlight the central issues that were considered as
pros and cons for the oral and systemic disease linkages. This Section carefully deliberated the quality
and quantity of the data on which we are seeking to
reach consensus, as to whether these reported associations between periodontal disease and systemic
conditions such as CVD, pneumonia, and adverse
pregnancy outcomes occur by chance as a result of
common underlying risk traits, behaviors, or exposures, or whether these associations survive as true
linkages independent of these potential confounders
and whether the increased risk is indeed attributable
to periodontal disease.
Members of the Section read and studied the review
titled Associations Between Periodontal Disease and
Risk for Atherosclerosis, Cardiovascular Disease, and
Stroke. A Systematic Review, by Frank A. Scannapieco, Renee Bush, and Susanna Paju. The focused
PICO question addressed by this evidence-based systematic review is: Does periodontal disease influence
the initiation/ progression of atherosclerosis and therefore cardiovascular disease, stroke, and peripheral vascular disease?
1. Does the Section agree that the evidence-based
systematic review is complete and accurate?
Yes. Members of the Section unanimously agreed that
the systematic review was complete and accurate as
of April 2002.

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2. Has any new information been generated or


discovered since the evidence-based search cut-off
date?
Yes, members of the Section identified several publications that directly or indirectly dealt with the topic
of the current systematic review.3-13
Authors of this review made the decision not to perform a meta-analysis on the existing studies due to
the small number of publications that specifically
addressed the focused PICO question. In addition, existing studies have disparate study design characteristics and use measures of exposure and outcomes that
would have limited the applicability and generalizability
of the meta-analysis. However, other authors using
other a priori study inclusion criteria and who addressed
other questions have analyzed and published 2 metaanalyses exploring the relationship between periodontal disease and cardiovascular diseases.3,4
One of these meta-analyses by Janket et al.3 included
9 cohort studies and concluded that periodontal disease is positively associated with an increased risk of
future cardiovascular diseases. In an analysis stratified
to individuals of 65 years of age the relative risk (RR)
was 1.44 (95% CI, 1.20 to 1.73). When outcome was
restricted to stroke only, the RR was 2.85 (95% CI, 1.78
to 4.56).
There is additional evidence from large epidemiological studies that periodontal disease is associated with
serum inflammatory markers that are considered significant surrogate markers of cardiovascular risk. Slade
et al. have reported that extensive periodontal disease
and body mass index (BMI) are jointly associated with
increased C-reactive protein (CRP) levels.5 In this
cross-sectional study of 5,562 subjects, periodontal
disease (defined as >30% of sites with probing depths
4 mm) was associated with increased serum CRP
concentration when adjusted for age, sex, diabetes,
cigarette smoking, and use of NSAIDs. Matilla et al. in
a pilot study of 35 subjects demonstrated that periodontal therapy reduced serum CRP levels.6
Malthaner et al. reported no significant differences
between periodontal disease parameters and coronary
artery disease (CAD) as assessed by angiogram.7 Beck
and Offenbacher have raised questions regarding
whether current clinical measures of periodontal disease
are sufficient to reflect the infectious and inflammatory
burden that periodontal disease poses as an exposure
for CVD risk.2 In light of the increasing evidence that
periodontal infections can have systemic effects, these
authors suggest that the definitions of periodontal disease as a systemic exposure be reconsidered to reflect
extent and severity, temporality, and systemic dissemination of the oral infectious and inflammatory burden.2
For example, Craig et al. demonstrated that antibodies

Scannapieco, Bush, Paju

to Porphyromonas gingivalis were positively associated with serum CRP levels (>2.08 mg/L) (OR = 5.6).8
In addition, multiple sites with periodontal disease progression were associated with an increased risk for high
CRP with an OR of 14.1.
Buhlin et al. reported a significant association between
self-reported bleeding gums, the presence of dentures
and cardiovascular disease.9 Hung et al. in a prospective 12-year study on 45,136 males demonstrated that
periodontal disease contributed to the risk of peripheral
vascular disease with a RR of 1.41 (95% CI, 1.12 to
1.77) and for any tooth loss during the follow-up period
the RR was 1.39 (95% CI, 1.07 to 1.82) controlling for
traditional risk factors for peripheral artery disease.10
Lpez et al. in a case-control study of 86 adults demonstrated a positive association between mean clinical
attachment level (OR = 3.17; 95% CI, 1.31 to 7.65),
mean probing depth (OR = 8.64; 95% CI, 1.22 to 61.2)
and the diagnosis of coronary heart disease (CHD).11
Joshipura et al. found an association between selfreported periodontal disease and stroke in a study of
41,380 subjects followed for 12 years.12 They reported
an adjusted hazards ratio (HR) of 1.57 (95% CI, 1.24
to 1.98) relating tooth loss and higher rate of ischemic
stroke, and an association was also seen between baseline periodontal disease history and ischemic stroke
(HR = 1.33; 95% CI, 1.03 to 1.70).
In addition to the relationship between periodontal
disease and atherosclerotic changes and ischemic
events, new findings indicate a potential relationship
with cardiac myopathy. Angeli et al. in a study of 104
patients with essential hypertension showed an association between severity of periodontitis and left ventricular mass.13
3. Does the Section agree with the interpretations
and conclusions of the reviewers?
Yes, the data for an association between periodontal
disease and atherosclerosis-induced disease are largely
due to case-control and epidemiologic studies, with few
prospective studies and are often limited to secondary
analyses of existing data sets. Measures of periodontal
disease vary considerably across studies, often relying
on variable and rather inexact or indirect assessments
to define case status, such as self-reported disease or
missing teeth as indices of periodontal disease as an
exposure. Clearly the results, although moderate in
nature, often show a positive association and those
studies with more complete periodontal data appear to
demonstrate stronger associations. Caution in the interpretation of these associations appears warranted, as
confounding factors such as smoking may obfuscate
these relationships. However, the high prevalence of
periodontal disease in the population may make these
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modest associations potentially important in a public


health context. To date it is unclear as to whether periodontal disease as an exposure can contribute to the
initiation of vascular atheromatous plaques, atheroma
maturation, or the subsequent rupture that precipitates
cardiovascular disease events. Pilot studies suggest that
periodontal therapy may have the potential to reduce
levels of surrogate serum markers of cardiovascular
disease, such as CRP.6,14 However, large-scale intervention trials examining the effects of periodontal therapy
on surrogate markers, or atheroma formation, or ultimately the direct demonstration of reduction in cardiovascular events have not been conducted. This represents
a critical deficit in our current knowledge base and needs
to be addressed in order to establish the medical necessity for periodontal care.
4. What further research needs to be done relative
to the focused questions of the evidence-based
review?
Scientifically, in order to elucidate whether the relationship between cardiovascular and periodontal disease is causal in nature we need data from controlled
interventional trials rather than observational studies.
For example, one observational study comparing CVD
rates of edentulous to dentate subjects concluded that
reduction in periodontal inflammation by tooth extraction (presumed due to periodontal disease) will not
prevent CVD.15 Such approaches are unable to determine the extent to which periodontal disease contributes to tooth loss as compared to other causes.
We recommend that large-scale multi-center placebocontrolled RCTs be conducted to determine whether the
treatment of periodontal infection reduces the risk of
cardiovascular events with mortality as the primary
outcome. One multi-centered pilot study is currently
underway to examine the effects of intervention on event
rate. Intervention studies could include a number of
periodontal treatment modalities to control infection and
inflammation.
Additional studies are recommended to determine
whether the prevention, presence, progression or treatment of periodontal infection and inflammation reduces
the biological markers of cardiovascular disease risk,
atheroma initiation, progression, and incidence of CVD
events. These studies would not only permit assessments of effects of periodontal treatment on the primary outcomes, but also would provide insights into
the mechanisms in the causal pathways.
Because of the high prevalence of periodontal disease and strength and consistency of the association,
it may serve as a confounder in other studies of CVD
risk and response to therapy. Therefore, we strongly
recommend that periodontal assessments should be a
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Volume 8 Number 1 December 2003

component of cardiovascular studies. It is recommended that efficient, inexpensive, and validated tools
be developed to assess periodontal disease as a systemic exposure for such large-scale trials.
5. How can the information from the
evidence-based review be applied to patient
management?
We concur with the current systematic review. It is consistent with the 2 recent meta-analyses that found a
statistically significant association between CVD and
periodontal disease. Furthermore, the association of
periodontal disease with ischemic stroke appears to
be stronger than periodontal disease and coronary
heart disease.
Pilot studies suggest periodontal treatment can reduce
risk factors for coronary heart disease, such as serum
CRP. However, RCTs are needed before any definitive
recommendations can be made regarding the treatment
of periodontal diseases to modulate heart disease.
A. There is evidence to suggest that periodontal disease is associated with cardiovascular disease, however
causality is unclear.
Level of Evidence: Moderate.
Rationale: Even though there are no level I RCTs,
the level of evidence was rated as moderate because
there are 24 level II studies (with some inconsistencies)
that demonstrate moderate associations between CVD
and periodontal disease. The conclusions of 2 recently
published meta-analyses are consistent with the current
systematic review and this conclusion.
B. There is currently insufficient evidence to show
that treatment of periodontal disease reduces the risk
of heart disease.
Level of Evidence:16 Insufficient.
Rationale: There are no level I RCTs or other studies
to show that treatment of periodontal infections lowers the risk of developing adverse cardiovascular (e.g.,
myocardial infarction) or cerebrovascular (e.g., stroke)
events.
Concluding Remarks
In the opinion of members of this Section, patients and
health care providers should be informed that periodontal
intervention may prevent the onset or progression of
atherosclerosis-induced diseases. This opinion is based
on 1) the strength and consistency of the association
between periodontal disease and CVD; 2) the overall
benefits of oral health; and 3) the negligible risk associated with periodontal therapy.
REFERENCES
1. Matitila KJ, Nieminen MS, Valtonen VV, et al. Association
between dental health and acute myocardial infarction.
Br Med J 1989;298:779-781.

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2. Beck JD, Offenbacher S. Relationships among clinical


measures of periodontal disease and their associations
with systemic markers. Ann Periodontol 2002;7:79-89.
3. Janket S-J, Baird AE, Chuang S-K, Jones JA. Metaanalysis of periodontal disease and risk of coronary heart
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Scannapieco, Bush, Paju

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1-11.

SECTION MEMBERS
Gary Greenstein, Group Leader
Thomas Hart
Steven Offenbacher, Chair
Brian L. Mealey
Denis Kinane, Secretary
Richard J. Nagy
Frank A. Scannapieco, Reviewer Maria E. Ryan
Robert J. Genco
Mark I. Ryder
Raul Garcia
Marc Shlossman
Barbara Steinberg

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