associations periodontal disease risk for artheosclerosis cardiovascular disease and stroke
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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 Buf falo, State University of New York, Buffalo, New York.
† Health Sciences Library.
Background: Recent studies implicate exposure to systemic con-ditions 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 diseaseand 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 identifyhuman studies that related variables associated with atherosclerosis toperiodontal disease. Searches were made for papers published from1966 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 infarc-
tion (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 meta-analysis of the data reported. Weighted mean differences, relativerisks, or odds ratios were compared for cohort studies.
Main Results1. 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 associ-ation 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 peri-
odontal disease complicates interpretation of results, as dopotential confounding risk factors common to both conditions.Reviewers’ Conclusions1. Periodontal disease may be modestly associated with athero-
sclerosis, MI, and CVD.2. Additional large-scale longitudinal epidemiologic and intervention
studies are necessary to validate this association and to deter-mine causality.
Ann Periodontol 2003;8:38-53 .
KEY WORDS
Atherosclerosis/etiology; inflammation; periodontal diseases/complications; risk factors; literature review.
BACKGROUND
Etiology of Atherosclerosis,Cardiovascular Disease,and StrokeThe major contributing factor in themajority of cases of cardiovasculardisease (CVD) and cerebrovasculardisease (stroke) is atherosclerosis.One of the outcomes of this diseaseprocess is the narrowing of the arter-
ies resulting from subendothelialdeposition of cholesterol, cholesterolesters, and calcium within the vesselwalls. These cholesterol-rich plaquesalso contain a variety of cell types,including fibroblasts and immunecells.1 Rupture of the atheroscleroticplaques yield thrombi that travel dis-tally to occlude the artery, resultingin myocardial infarction or stroke.
Several factors increase the riskfor atherosclerosis including a pre-
disposition for elevated levels of cho-lesterol and triglyceride in the blood;high blood pressure; diabetes; andcigarette smoking.
Normal cells obtain most of thecholesterol they need for normalfunctioning by taking up cholesterolfrom the blood through receptor-mediated endocytosis. Cholesterolis transported in the blood boundto low-density lipoproteins, or LDLs.These LDLs bind to specific trans-membrane receptor proteins for
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transport into the cell. Cholesterol uptake is blockedin some people (e.g., due to an apolipoprotein Edefect), and excess cholesterol accumulates in theblood to eventually form atherosclerotic plaques. If these plaques occlude blood flow in brain arteries, theresult can be stroke; if they occur in coronary arter-
ies, it can lead to myocardial infarction.
Role of Inflammation in Atherosclerosis,Cardiovascular Disease, and StrokeA recent and growing literature implicates infection,local and/or systemic inflammation, and possiblyautoimmunity in the pathogenesis of atherosclerosis.2
Arterial inflammation may be locally increased by lipidimbalances, hemodynamic stress, and immune reac-tions directed against the vascular wall, eventuallyleading to the formation of complicated atheroscleroticlesions.3 This inflammation-mediated damage may ini-
tiate or contribute to the progression of the athero-sclerotic plaque. A number of pathogens appear to beassociated with atherosclerotic plaques, and alterationsin the immune responsiveness may compromise clear-ance of the organism from these plaques. One of thebest studied of these associations involves Chlamydia pneumoniae , a common intracellular bacterium thatcauses pneumonia and milder respiratory tract infec-tions. Recently, C. pneumoniae DNA and proteins havebeen detected in arteries of patients with giant cellarteritis,4 and in endarterectomy samples.5 Elevatedantibody levels against C. pneumoniae have beenmeasured in patients with coronary heart disease com-
pared to controls.6Serum inflammatory biomarkers such as C-reactive
protein (CRP) appear to be elevated in subjects withatherosclerosis.7 Other suggested biomarkers includefibrinogen, cell adhesion molecules, and various inflam-matory cytokines.8 In fact, models using CRP togetherwith lipid profiles appear to predict risk for cardiovas-cular events better than the use of lipids alone.
RATIONALE
The first suggestion that periodontal inflammation maybe related to atherosclerosis came in a paper pub-
lished in 1988.
9
These investigators compared the oralhealth (measured by the Community Periodontal Indexof Treatment Needs) of 211 male patients in Yugoslaviawho experienced an MI with 336 control patients. Theynoted that the MI group had worse periodontal healththan did the control group. Subsequent case-controlstudies also showed a relationship of poor oral healthto MI.10-13 In addition, risk indicators for cardiovasculardisease have also been shown to be elevated in sub-
jects with periodontitis.14,15 There has been an ever-increasing literature in response to this notion. Althoughthe majority of publications have suggested an asso-ciation between poor oral health and atherosclero-
sis,9,11,16-26 several epidemiologic studies have foundno such relationship.13,26-28
The goal of this systematic review was to identifyall literature pertinent to this issue, to critically evaluateit and understand the current state of knowledge on thissubject, and to point out directions for additional
research.
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)?”
SEARCH PROTOCOL
Data Sources and Search StrategyThe search strategy was defined to include randomizedcontrolled clinical trials (RCTS), longitudinal, cohort,
and case-control studies.Search terms: Searches were run by one of thereviewers (RB) using Ovid Search software of MED-LINE (1966-March 2002), MEDLINE Daily Update, andCochrane Controlled Trials Register (CCTR) updatedto first quarter of 2002. MEDLINE and MEDLINE DailyUpdate were searched using medical subject headings(MeSH terms). Reference lists of previously publishedreview articles were also searched. All MeSH termsemployed were exploded to expand retrieval to thoserecords that were assigned the more narrow relatedMeSH term. The CCTR database and Pre-MEDLINErequired use of keywords (we used both American and
British spellings). All searches included the term “andhuman.”
MeSH terms: Cardiovascular diseases, or heart dis-eases, or arteriosclerosis, or cerebrovascular disorders,or carotid artery diseases, or peripheral vascular dis-eases, or cerebrovascular accident, or hypercholes-terolemia.
Oral conditions: Periodontal diseases, tooth diseases,or dental plaque index.
Key words: Arteriosclerosis, or atherosclerosis, orcarotid artery disease, or myocardial infarction, orcoronary disease, or cardiovascular disease, or periph-
eral vascular disease, or hypercholesterolemia, orhypercholesterolaemia, or cerebrovascular disorder, orcerebrovascular 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 reviewwere those that recruited participants with atheroscle-rosis, myocardial infarction (MI), stroke, or peripheralvascular disease. Oral conditions considered includedperiodontal disease (as measured by assessments of gingival inflammation, probing depth, clinical attach-ment loss, and/or radiographic bone loss). Our search
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strategy also considered studies that tested the effectof periodontal intervention on the initiation and pro-gression of atherosclerosis, MI, stroke, or peripheralvascular disease.
Exclusion criteria: The search was limited only tostudies of humans.
Outcomes: The following outcome measures wereassessed:
1. Primary outcome: increased incidence of MI orstroke associated with periodontal disease.
2. Secondary outcomes: deficient measures of heartfunction or surrogates of cardiovascular risk, such asmeasures of endothelial function, intima-media wall thick-ness, vascular calcification, blood lipids, or C-reactiveprotein 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 AnalysisTitles and abstracts of articles obtained using the abovedescribed search strategy were screened by two inde-pendent readers (FAS and SP) and checked for agree-ment. The full text of the articles judged by title andabstract to be relevant (by either FAS or SP) were readand independently assessed against the stated inclusioncriteria.
For cohort studies that measured differences in ratesof disease between the group with oral disease andthe group without oral disease, weighted mean differ-ences, relative risks or odds ratios were compared. No
published randomized controlled clinical trials evalu-ating primary outcomes were identified during thecourse of this search.
Because of the heterogeneity in study design, meth-ods of outcome measures, and target populations, noeffort was made to perform a meta-analysis of theincluded studies.
Ranking of StudiesIncluded papers were graded according to previouslyreported classifications.29,30
1. Systematic review of randomized controlled clinicaltrials. RCTs with narrow confidence intervals.
2. Randomized controlled clinical trial. Low qualitysystematic review.
3. Case-control study. Systematic review of case-controlstudies.
4. Cross-sectional study.
RESULTS AND DISCUSSION
Following the described search strategy, MEDLINEsearching yielded 1,502 articles (1,020 in the Englishlanguage). In addition, 1 article was retrieved from theMEDLINE Daily Update, 19 from the Pre-MEDLINEand 4 from CCTR. Titles and abstracts were read andthe full text of all articles deemed relevant were
obtained and reviewed. This process resulted in theselection of 31 articles that attempted to evaluate theassociation of periodontal disease to CVD, stroke, orperipheral 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 oralhealth and atherosclerosis-induced heart disease beganwith case and case-control studies in the 1980s. Sincethen 4 additional case-control studies have been pub-lished. Of the 5 case-control studies (Table 1), 4reported a positive association between indicators of poor dental health and outcomes of atherosclerosis(CVD).9-11,16 The one study reporting the absence of apositive association was of very elderly subjects.13 Takentogether, these studies support a positive associationbetween the poor oral health and the prevalence of car-diovascular events. In some cases, the evidence points
to an association with periodontal disease.Stimulated by these first case-control studies, 15cross-sectional studies have since been published(Table 2).17-28,31-33 Of these, 11 studies support amodest association of periodontal disease with CVD,after controlling for other cardiovascular risk factors,particularly smoking. Because few studies use thesame oral assessment measures, it is not possible toperform a valid meta-analysis by combining data fromthese studies. Most studies were retrospective in design.To date, results from a prospective, longitudinal epi-demiologic study have not been reported.
In addition, 4 other studies have shown a positive
association between periodontal disease andstroke,20,34-36 and another study has associated peri-odontal disease with peripheral vascular disease37
(Table 3).In addition to the aforementioned epidemiologic stud-
ies, several other studies14,15,38-41 have reported anassociation of periodontal disease with various para-meters causally linked with the pathogenesis of ather-osclerosis-induced disease (Table 4). These studiesdemonstrate elevated levels of C-reactive protein, fib-rinogen, white blood cells, cholesterol, and cytokinesin association with periodontal disease. Results of such
studies suggest possible mechanisms that link peri-odontal disease to the etiology of atherosclerosis.One of the limitations of this analysis is the recog-
nition of the great heterogeneity between studies inassessment of oral disease, making comparision of results difficult. An internationally accepted and stan-dardized protocol for the assessment of oral health islacking. Limiting consideration only to studies thatused clinical attachment levels as a measure of peri-odontal disease history (a commonly accepted meas-ure of periodontal damage) reveals general consensusof a positive association between the extent of attach-ment loss and CVD.12-15
40
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Table 1.
Case-Control Studies Relating Oral Health to Cardiovascular Disease
Cardiovascular Study
Reference Study Population Oral Assessment Assessment Conclusions Ranking
Simonka et al.9 Cases: 211 males with “KEP” index Previously Significant difference in CPITN 31988 previous heart attack. (= DMF: caries, diagnosed MI and demand for periodontal
Controls:336 age- missing, and surgery in patients >50 years
matched patients filled teeth), old with heart attack.
without heart attack. CPITN index. No difference in DMF
between cases and controls.
Mattila et al.10 Cases: 40 males ≤50 Dental Severity Index Evidence of MI from Dental health significantly 3
1989 years old; 60 males (sum of scores for EKG and elevated worse in patients with
and females
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Table 2.
Cross-Sectional and Longitudinal Studies
Reference Study Population Oral Assessment
DeStefano et al.17 1993 9,760 subjects enrolled in the N decayed permanent teeth. Per iodontalNational Health and Nutr ition Survey classification (no disease; gingivitis; per iodontitis
(NHANES) I from 1971 to with >4 mm pockets; no teeth). Periodontal
1974. Follow-up until 1982. 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 par ticipants of the Health Self-reported number of teeth,
Professionals Follow-up Study and history of periodontal disease
(58% were dentists).
Beck et al.20 1996 203 cases; 940 controls from VA Alveolar bone loss measured from
Dental Longitudinal Study component radiographs measured using Schei ruler ;
of the Normative Aging Study. 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-2-
naphthylamide 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 Periodontal disease classified as none,
Nutrition Canada Survey. mild gingivitis, severe gingivitis,
obvious pockets, loose
teeth, and edentulous.
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Table 2. (continued)
Cross-Sectional and Longitudinal Studies
Major Findings or Odds Ratio
Cardiovascular Assessment (OR) or Risk Ratio (RR) (95% CI) Conclusions Study Grade
Admission to hospital for RR 1.72 (1.10-2.68) when Dental disease is associated with 4CHD treatment.Mortality periodontitis compared a small increased risk of CHD.
due to coronary heart disease. to CHD.
Screening examination using Prevalence of ischemic heart A weak but statistically significant 4
questionnaires and interviews disease was correlated with the associat ion between missing
about previous disease; chest number of missing teeth;around teeth and ischemic
X-rays, EKG, blood pressure. 10% when less than 1/2 teeth heart disease.
Subjects with any suggestive finding lost and around 20% when at
were re-examined with clinical least 1/2 teeth were lost.
examination and diagnosis by
physician. CHD defined as
angina pectoris or previous MI.
Fatal/non-fatal MI, sudden death. Men with periodontal disease and A small association between 4
Subjects with revascularization with 0-10 teeth, as compared to tooth loss and CHD risk; no
procedures excluded. men with 25+ teeth, RR = overall association between
1.67 (1.03-2.71). No association per iodontal disease and CHD.
among men without periodontal
disease, RR = 1.11(0.74-1.68).
Total CHD determined as cases of Incidence odds ratios: Periodontal disease associated 4
non-fatal MI, a ngina pectoris, a nd CHD Bone loss and total CHD 1.5, with a moderate risk
deaths. Stroke diagnosed by means Bone loss and fatal CHD 1.9, of CHD/stroke.
of history and physical examination. Bone loss and stroke 2.8.
Diagnosis of MI, bypass surgery, Significant association between CHD Several oral health variables 4
clinical angina, EKG, serum enzyme and poor oral health in independent are risk indicators for CHD.
levels, angiography;positive response living subjects. OR for 1-14 teeth
to treatment for heart disease. 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).
Self-reported MI. Relative to 0% category, the unadjusted Results support an association 4
odds of heart attack increased with between periodontal disease
each higher category of attachment and coronary heart disease.
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).
Death attributed to coronary The relation between dental health (sev- These data indicate that 4
heart and cerebrovascular disease ere gingivitis and edentulous status) poor dental health is
and the risk of fatal CHD and CVD associated with an
was (rate ratios-RR) 2.15 (1.25-3.72) increased risk of
and 1.90 (1.17-3.10), respectively, as fatal CHD.
adjusted for confounding variables. (continued)
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Table 2. (continued)
Cross-Sectional and Longitudinal Studies
Reference Study Population Oral Assessment
Beck et al.24 2001 6,017 persons from the Periodontitis was defined by extentAtherosclerosis Risk in of attachment loss ≥3 mm: none/mild
Communities Study 1996. (
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Table 2. (continued)
Cross-Sectional and Longitudinal Studies
Major Findings or Odds Ratio
Cardiovascular Assessment (OR) or Risk Ratio (RR) (95% CI) Conclusions Study Ranking
Carotid artery intima-media Severe periodontitis (OR 1.31, Periodontitis may influence 4wall thickness (IMT) ≥1 mm. CI 1.03 -1.66) was associated atheroma formation.
with IMT ≥1 mm,while adjusting
for the other factors.
Death due to CVD. The sum of scores for number of Poor dental health and smoking 4
missing teeth,apical lesions, car ies are r isk indicators of death
lesions, and marginal bone loss was due to CVD.
significantly correlated to fatal coro-
nary events in subjects ≤45 years old.
Death from CHD or hospitalization Neither gingivitis nor periodontitis This study did not find 4
due to CHD, or revascularization was associated with a statistically convincing evidence of a
procedures, obtained from death significant increased risk for CHD. causal association between
certificates and medical records. periodontal diseaseand CHD risk.
Death from CHD, or hospitalization Confirmed elimination of Reduction in periodontal 4
due to CHD, or revascularization chronic dental infections (by inflammation by
procedures, obtained from death full-mouth dental extraction) tooth extraction
certificates and medical records. did not lead to a decreased risk will not prevent CHD.
of experiencing a CHD event.
A cardiovascular event was confirmed No statistical association between Self-reported periodontal 4
after examination of all information cardiovascular death or stroke and disease is not an independent
by an end points committee self-reported periodontal disease predictor of subsequent
blinded to participants’ periodontal at baseline, compared to cardiovascular disease.
disease status. Nonfatal stroke was those who did not.
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.
History of MI and/or anginal syndrome A significant association between The generation of higher choles- 4
with angiographic evidence of CPITN score 4 and terol blood levels is proposed
significant coronary disease, or hypercholesterolemia. as a possible link between
suffer from atherosclerotic risk chronic periodontal inflam-
factors; i.e., diabetes (fasting glucose). mation and atherosclerosis.
Abnormal ECG findings. Individuals with
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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
Syrjanen et al.34 1989 Case-control study of 40 patients with ischemic Total dental index that measured N carious lesions,
cerebral infarction under the age of 50, and severity of periodontitis, N periapical lesions and
40 randomly selected community controls pericoronitis.The presence of subgingival calculus or
matched for gender and age. suppuration in the gingival pockets was measured.
Beck et al.20 1996 203 cases and 940 controls from VA Dental Alveolar bone loss measured from radiographs
Longitudinal Study component of the measured using Schei ruler ; worst clinical PD
Normative Aging Study. per tooth.
Loesche et al.35 1998 Cross-sectional study of 401 veterans N teeth (0-14 and 15-28 ); PD, attachment level, and
≥60 years of age. gingival recession; plaque index; gingival bleeding;
evaluation of salivary flow and xerostomia.
Wu etal.36 2000 9,962 par ticipants enrolled in NHANES-I and Periodontal status was grouped into one of the
follow-up study. 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 Radiographic measures of alveolar bone loss estimated
and periodontal disease by analyzing data from intraoral periapical films taken at baselinefrom the Normative Aging Study and Dental using Schei ruler.
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.
Additional large-scale longitudinal epidemiologic andinterventional studies are necessary to validate thisassociation and to determine if the association is
causal.Presently, insufficient evidence is available to justifyperiodontal intervention to prevent the onset or pro-gression of atherosclerosis-induced diseases.
FUTURE DIRECTIONS FOR RESEARCH
Studies to date provide equivocal evidence that peri-odontal disease has a causal link to atherosclerosis.Further research must be conducted to definitivelyestablish the role of periodontal disease in the etiologyof athersclerosis. Randomized controlled clinical trialsthat evaluate the effects of periodontal intervention(that may include mechanical, chemical, or host mod-
ulatory approaches) in the prevention of atheroscleroticdisease as well as in the management of patients suf-fering the effects of atherosclerosis-induced diseases
(e.g., myocardial infarction, stroke) are necessary toprove or disprove this link.
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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 aor to-cervical angiography Poor oral health was more common in subjects with 3
or by detection of brain stem infarction or ischemic cerebrovascular disease in patients 6 mm compared to 12% in subjects without
scans, and physical and neurologic CVA (P = 0.028). Dentate subjects with CVA had more
examinations. 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 Compared with no periodontal disease, the relative risks 4
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cause of death due to CVA or 1 or more stroke were 1.24 (0.74-2.08) for gingivit is ,2.11 (1.30-3.42)
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follow-up period with discharge
Subjects with periodontal disease at baseline Periodontal disease emerged as a significant independent 4
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Table 4.
Relationships of Markers of Atherosclerosis Associated with Human Periodontal Disease
Study
Reference Study Population Outcome Conclusions Ranking
Kweider et al.38 Case control. Dental indices (plaque index, gingival Inflammatory dental disease 41993 Cases: 50 consecutive patients index,CPITN) correlated significantly may influence fibrinogen
attending dental hospital. with fibrinogen and WBC count (GI level and WBC count.
Controls: 50 subjects with and fibrinogen K = 3.17 and GI and
healthy periodontium WBC K = 3.38).
recruited from hospital
patients and staff.
Ebersole et al.15 40 subjects with per iodontitis C-reactive protein (CRP) and haptoglobin Localized per iodontal 4
1997 (radiographic evidence of (Hp) weresignificantly increased in infections result in
bone loss, pockets >5 mm, serum from periodontal patients increased inflammation
bleeding on probing) were compared to healthy controls (P
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16. Emingil G, Buduneli E, Aliyev A, Akilli A, Atilla G. Asso-ciation between periodontal disease and acute myocar-dial infarction. J Periodontol 2000;71:1882-1886.
17. DeStefano F, Anda RF, Kahn HS, Williamson DF, RussellCM. Dental disease and risk of coronary heart diseaseand mortality. Br Med J 1993;306:688-691.
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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 coronaryheart 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 Peri- odontol 1996;67:1123-1137.
21. Loesche WJ, Schork A, Terpenning MS, Chen YM,Dominguez BL, Grossman N. Assessing the relationshipbetween dental disease and coronary heart disease inelderly U.S. veterans. J Am Dent Assoc 1998;129:301-311.
22. Arbes SJ Jr, Slade GD, Beck JD. Association betweenextent of periodontal attachment loss and self-reportedhistory of heart attack: An analysis of NHANES III data.
J Dent Res 1999;78:1777-1782.23. Morrison HI, Ellison LF, Taylor GW. Periodontal diseaseand risk of fatal coronary heart and cerebrovascular dis-eases. J Cardiovasc Risk 1999;6:7-11.
24. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM,Offenbacher S. Relationship of periodontal disease tocarotid artery intima-media wall thickness: The Ather-osclerosis Risk in Communities (ARIC) study. Arterioscler Thromb Vasc Biol 2001;21:1816-1822.
25. Jansson L, Lavstedt S, Frithiof L, Theobald H. Relation-ship between oral health and mortality in cardiovascu-lar 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 andthe elimination of chronic dental infections. J Am Dent Assoc 2001;132:883-889.
28. Howell TH, Ridker PM, Ajani UA, Hennekens CH, ChristenWG. Periodontal disease and risk of subsequent cardio-vascular disease in U.S. male physicians. J Am Coll Car- diol 2001;37:445-450.
29. Newman MG, Hujoel PP. Statement of purpose and meth-ods. J Evid Based Dent Prac 2001;1:3A-5A.
30. Kahn KS, Riet GT, Popay J, Nixon J, Kleijnen J. Under-taking systematic reviews of research on effectiveness.Phase 5. Study quality assessment. In: University of York NHS Centre for Reviews and Dissemination ; 2001. Avail-able 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 diseaseand severe periodontal disease. J Clin Periodontol 2001;28:865-868.
32. Takata Y, Ansai T, Matsumura K, et al. Relationshipbetween tooth loss and electrocardiographic abnormal-ities in octogenarians. J Dent Res 2001;80:1648-1652.
33. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.Pre-existing cardiovascular disease and periodontitis: Afollow-up study. J Dent Res 2002;81:186-191.
34. Syrjänen J, Peltola J, Valtonen V, Iivanainen M, Kaste M,Huttunen JK. Dental infections in association with cere-bral 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 diseaseand cerebral vascular accident in elderly United Statesveterans. Ann Periodontol 1998;3:161-174.
36. Wu T, Trevisan M, Genco RJ, Dorn JP, Falkner KL,Sempos CT. Periodontal disease and risk of cerebrovas-cular 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 dis-ease and peripheral vascular disease. Am J Surg 1998;176:153-157.
38. Kweider M, Lowe GD, Murray GD, Kinane DF, McGowanDA. Dental disease, fibrinogen and white cell count; linkswith myocardial infarction? Scott Med J 1993;38:73-74.
39. Wakai K, Kawamura T, Umemura O, et al. Associationsof medical status and physical fitness with periodontaldisease. 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 peri-odontal 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 ele-vated systemic C-reactive protein level. J Periodontol 2001;72:1221-1227.
Correspondence: Dr. Frank A. Scannapieco, Department of OralBiology, 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 rela-
tively common, chronic, multifactorial conditions. Theconcordant linkages or associations between thesecoincident conditions may reflect chance occurrence,
the sharing of a common antecedent susceptibility orresistance traits, common behaviors or exposures, or
the influence of one condition on the other. Further-more, both conditions have heterogeneous clinical pre-sentations 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 cardio-
vascular disease among chronic periodontitis patientswas higher than the general population was reportedover a decade ago suggesting that these two conditions
tend to cluster or self-aggregate within the popula-tion.1 Upon first consideration, it would appear that
these linkages of both periodontal disease and car-
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diovascular disease within subjects might easily beexplained by the presence of common behaviors or
traits that increase the risk for both conditions, suchas smoking or obesity. Thus, the challenge of any study
design and analytical experimental approach aimed atquantifying the relative contribution of periodontal dis-
ease to cardiovascular disease is that the study needsto include a wide range of additional risk factors ormarkers that enable one to dissect out and quantify thatportion of the risk that is specifically attributable to
periodontal disease. That is, the effects of periodontaldisease need to be considered in the presence of full
measurements of other confounding or effect-modifyingvariables, being as inclusive as possible. For this rea-son, studies must usually be fairly large and epidemi-
ologic in nature, usually requiring at least 10 cases ineach subcell to adequately adjust or “statistically cor-
rect for” each possible risk factor that needs to be con-
sidered as a possible modifier of either periodontaldisease or cardiovascular disease. As a consequence
the initial analyses showed associations, which couldnot 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 review-ers were ever cognizant of the central importance of examining for and evaluating the quality of the datawith regards to these critical issues of assessing thepotential contribution of confounders and covariates.
It is in this context that the evidence for an associa-tion between periodontal disease and systemic condi-tions, such as cardiovascular disease, pneumonia, andadverse pregnancy outcomes has been uniformly andsystematically considered. Furthermore, it has nowbeen acknowledged that the manner in which peri-odontal disease is defined as a systemic exposure;e.g., as a condition that may contribute risk for CVD,may differ from traditional classifications of periodontaldisease. These traditional classifications use signs andsymptoms (such as bleeding scores) as an index of exposure to quantify the risk for a tooth-related out-come, for example an increase in probing depth orbone loss and not a systemic disease outcome. As yetanother example, bleeding sites and probing depthsmay be a better reflection of systemic exposure thanattachment and bone loss, depending on the outcomeof interest.2 Thus, the definition of periodontal diseasewhich serves to define a periodontal case as a sys-tematic exposure is a simplified, clinical measurementrepresentation of the triad of periodontal disease com-ponents: periodontal infection, inflammation, and clin-ical signs. For this reason, the diversity in the definitionsof periodontal case status that has been used to defineperiodontal exposure among different studies is not a
failure to recognize or apply traditional, uniform defi-nitions, but rather is a data-driven reassessment of thechanging definitions or clustering of clinical signs thatbest describe the relationships.
Despite these conceptual limitations that require aparadigm shift in considering periodontal disease as
a possible etiologic contributor to cardiovasculardisease, the body of evidence continues to accrue
supporting a modest association even after thought-
ful and complete statistical methodological correctionor adjustment for other risk factors, such as smoking.
However, residual confounding may still be present inthat these methods have not adequately captured the
appropriate measure of periodontal disease as an
exposure that increases the risk of a given systemicdisease or condition. But this is always a character-
istic of epidemiologic, observational, and case-controlstudy designs. It is important to note that overcor-
rection for confounders can easily occur in these ana-lytical approaches, as well. For example, the effectsof cholesterol on the risk for heart disease in large
data sets can be easily missed or nullified if non-rel-evant 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 link-ages. This Section carefully deliberated the quality
and quantity of the data on which we are seeking to
reach consensus, as to whether these reported asso-
ciations between periodontal disease and systemicconditions such as CVD, pneumonia, and adverse
pregnancy outcomes occur by chance as a result of common underlying risk traits, behaviors, or expo-
sures, or whether these associations survive as truelinkages 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 andRisk for Atherosclerosis, Cardiovascular Disease, and
Stroke. A Systematic Review,” by Frank A. Scanna-
pieco, Renee Bush, and Susanna Paju. The focusedPICO question addressed by this evidence-based sys-
tematic review is: “Does periodontal disease influencethe initiation/ progression of atherosclerosis and there-
fore cardiovascular disease, stroke, and peripheral vas-
cular disease?”
1. Does the Section agree that the evidence-based
systematic review is complete and accurate?
Yes. Members of the Section unanimously agreed thatthe 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 publi-
cations that directly or indirectly dealt with the topic
of the current systematic review.3-13
Authors of this review made the decision not to per-form a meta-analysis on the existing studies due to
the small number of publications that specifically
addressed the focused PICO question. In addition, exist-
ing studies have disparate study design characteris-
tics 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 meta-
analyses exploring the relationship between periodon-
tal disease and cardiovascular diseases.3,4
One of these meta-analyses by Janket et al.3 included9 cohort studies and concluded that periodontal dis-
ease 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 epidemiolog-
ical studies that periodontal disease is associated with
serum inflammatory markers that are considered sig-
nificant surrogate markers of cardiovascular risk. Slade
et al. have reported that extensive periodontal diseaseand 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 peri-
odontal 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 Beckand 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 dis-
ease as a systemic exposure be reconsidered to reflect
extent and severity, temporality, and systemic dissem-
ination of the oral infectious and inflammatory burden.2
For example, Craig et al. demonstrated that antibodies
to Porphyromonas gingivalis were positively associ-
ated with serum CRP levels (>2.08 mg/L) (OR = 5.6).8
In addition, multiple sites with periodontal disease pro-
gression 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 denturesand cardiovascular disease.9 Hung et al. in a prospec-
tive 12-year study on 45,136 males demonstrated thatperiodontal disease contributed to the risk of peripheral
vascular disease with a RR of 1.41 (95% CI, 1.12 to1.77) and for any tooth loss during the follow-up periodthe RR was 1.39 (95% CI, 1.07 to 1.82) controlling for
traditional risk factors for peripheral artery disease.10
López et al. in a case-control study of 86 adults demon-strated 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).11Joshipura et al. found an association between self-
reported periodontal disease and stroke in a study of
41,380 subjects followed for 12 years.12 They reportedan adjusted hazards ratio (HR) of 1.57 (95% CI, 1.24
to 1.98) relating tooth loss and higher rate of ischemicstroke, and an association was also seen between base-line 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 104patients with essential hypertension showed an asso-ciation between severity of periodontitis and left ven-tricular 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 largelydue to case-control and epidemiologic studies, with few
prospective studies and are often limited to secondaryanalyses of existing data sets. Measures of periodontal
disease vary considerably across studies, often relyingon variable and rather inexact or indirect assessmentsto define case status, such as self-reported disease ormissing teeth as indices of periodontal disease as an
exposure. Clearly the results, although moderate innature, often show a positive association and those
studies with more complete periodontal data appear todemonstrate stronger associations. Caution in the inter-pretation of these associations appears warranted, as
confounding factors such as smoking may obfuscatethese relationships. However, the high prevalence of
periodontal disease in the population may make these
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modest associations potentially important in a publichealth context. To date it is unclear as to whether peri-
odontal disease as an exposure can contribute to theinitiation of vascular atheromatous plaques, atheroma
maturation, or the subsequent rupture that precipitatescardiovascular disease events. Pilot studies suggest that
periodontal therapy may have the potential to reducelevels of surrogate serum markers of cardiovasculardisease, such as CRP.6,14 However, large-scale interven-tion trials examining the effects of periodontal therapy
on surrogate markers, or atheroma formation, or ulti-mately the direct demonstration of reduction in cardio-
vascular events have not been conducted. This representsa critical deficit in our current knowledge base and needsto be addressed in order to establish the medical neces-
sity for periodontal care.
4. What further research needs to be done relative
to the focused questions of the evidence-basedreview?
Scientifically, in order to elucidate whether the rela-
tionship between cardiovascular and periodontal dis-ease 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 thatreduction in periodontal inflammation by tooth extrac-
tion (presumed due to periodontal disease) will not
prevent CVD.15 Such approaches are unable to deter-
mine the extent to which periodontal disease con-
tributes to tooth loss as compared to other causes.We recommend that large-scale multi-center placebo-
controlled 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 treat-
ment of periodontal infection and inflammation reducesthe biological markers of cardiovascular disease risk,
atheroma initiation, progression, and incidence of CVD
events. These studies would not only permit assess-
ments of effects of periodontal treatment on the pri-mary outcomes, but also would provide insights into
the mechanisms in the causal pathways.
Because of the high prevalence of periodontal dis-
ease 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
component of cardiovascular studies. It is recom-
mended that efficient, inexpensive, and validated tools
be developed to assess periodontal disease as a sys-temic 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 con-sistent with the 2 recent meta-analyses that found a
statistically significant association between CVD andperiodontal disease. Furthermore, the association of
periodontal disease with ischemic stroke appears tobe stronger than periodontal disease and coronaryheart disease.
Pilot studies suggest periodontal treatment can reducerisk factors for coronary heart disease, such as serumCRP. However, RCTs are needed before any definitive
recommendations can be made regarding the treatmentof periodontal diseases to modulate heart disease.
A. There is evidence to suggest that periodontal dis-ease is associated with cardiovascular disease, howevercausality is unclear.
Level of Evidence: Moderate.Rationale: Even though there are no level I RCTs,
the level of evidence was rated as “moderate” becausethere are 24 level II studies (with some inconsistencies)that demonstrate moderate associations between CVD
and periodontal disease. The conclusions of 2 recentlypublished 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 low-ers 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 andhealth care providers should be informed that periodontal
intervention may prevent the onset or progression of atherosclerosis-induced diseases. This opinion is basedon 1) the strength and consistency of the association
between periodontal disease and CVD; 2) the overallbenefits of oral health; and 3) the negligible risk asso-ciated with periodontal therapy.
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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 ShlossmanBarbara Steinberg