Associations Periodontal Disease Risk for Artheosclerosis Cardiovascular Disease and Stroke

8/20/2019 Associations Periodontal Disease Risk for Artheosclerosis Cardiovascular Disease and Stroke

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Volume 8 • Number 1 • December 2003

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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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Ann Periodontol Scannapieco, Bush, P

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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Periodontal Disease and Risk for Atherosclerosis, Cardiovascular Disease, and Stroke Volume 8 • Number 1 • December 2003

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)


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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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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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


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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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

the following criteria: death certificate with (95% confidence intervals) for incident nonhemorrhagic

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)

hospital/nursing home stays dur ing the for per iodontitis, and 1.41 (0.96-2.06) for edentulousness.

follow-up period with discharge

Subjects with periodontal disease at baseline Periodontal disease emerged as a significant independent 4

had a 2.27 increased r isk of developing r isk factor for PVD in a multivar iate analysis thatPVD (95% CI 1.32-3.9, P = 0.003) after adjusted for other established risk factors.

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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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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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50

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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2. Beck JD, Offenbacher S. Relationships among clinicalmeasures of periodontal disease and their associationswith systemic markers. Ann Periodontol 2002;7:79-89.

3. Janket S-J, Baird AE, Chuang S-K, Jones JA. Meta-analysis of periodontal disease and risk of coronary heartdisease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:559-569.

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5. Slade GD, Ghezzi EM, Heiss G, Beck JD, Riches E,Offenbacher S. Relationship between periodontal dis-ease and C-reactive protein among adults in the Ather-osclerosis Risk in Communities Study. Arch Intern Med 2003;26;163:1172-1179.

6. Mattila K, Vesanen M, Valtonen V, et al. Effect of treatingperiodontitis on C-reactive protein levels. A pilot study.BMC Infect Dis 2002;2(Dec 10):30-?

7. Malthaner SC, Moore S, Mills M, et al. Investigation of the association between angiographically defined coro-nary artery disease and periodontal disease. J Peri-

odontol 2002;73:1169-1176.8. Craig RG, Spittle MA, Levin NW. Importance of peri-odontal disease in the kidney patient. Blood Purif 2002;20:113-119.

9. Buhlin K, Gustafsson A, Håkansson J, Klinge B. Oralhealth and cardiovascular disease in Sweden. Results of a national questionnaire survey. J Clin Periodontol 2002;29:254-259.

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11. López R, Oyarzún M, Narajo C, Cumsille F, Ortiz M,Baelum V. Coronary heart disease and periodontitis–acase control study in Chilean adults. J Clin Periodontol 2002;29:468-473.

12. Joshipura KJ, Hung HC, Rimm EB, Willett WC, Ascherio A.Periodontal disease, tooth loss, and incidence of ischemicstroke. Stroke 2003;34:47-52.

13. Angeli F, Verdecchia P, Pellegrino C, et al. Associationbetween periodontal disease and left ventricle mass inessential hypertension. Hypertension 2003;41:488-492.

14. Iwamoto Y, Nishimura F, Soga Y, et al. Antimicrobial peri-odontal treatment decreases serum C-reactive protein,tumor necrosis factor-alpha, but not adiponecin levels inpatients with chronic periodontitis. J Periodontol 2003;74:1231-1236.

15. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.Examining the link between coronary heart disease and

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evidence-based approach in a periodontal therapy con-temporary science workshop. Ann Periodontol 2003;8:1-11.

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 ShlossmanBarbara Steinberg

Documents

Associations Periodontal Disease Risk for Artheosclerosis Cardiovascular Disease and Stroke