Cardiovasculer and Pd

8/10/2019 Cardiovasculer and Pd

1/13

2012; 46, no.2: 131142 131

Periodontal and cardiovascular diseases

Periodontal and cardiovascular diseases:Statistical or causal association?A review and analysis using Hills criteria for causationSotirios Kotsovilis*, Dr Med, DDS, MS;Lynne H. Slim, RDH, MS

ABSTRACTObjective:The objective of the review was to summarize and

critically evaluate the available evidence, using systematic reviewsand meta analyses, concerning the statistical strength and the nature(statistical and/or causal) of the association between periodontaland cardiovascular diseases. Methods:The statistical associationbetween periodontal and cardiovascular diseases was assessed after

searching PubMedand The Cochrane Library(CENTRAL) databasesfor systematic reviews and meta analyses, published in English upto and including August 2011. The hypothesis stating a causalassociation between periodontal and cardiovascular diseases wasexamined using Bradford Hills criteria for causation.Results andDiscussion:An independent statistically significant association ofweak to moderate strength was found between periodontal andcardiovascular diseases, after adjusting for potential confoundingfactors, such as advancing age, gender, race, smoking, hypertension,diabetes, indicators of socioeconomic status, stress, obesity, and lipidrich diet. The present analysis demonstrated only a partial fulfillmentof Bradford Hills criteria for causation. Conclusions:Periodontaldiseases have an independent statistically significant associationwith cardiovascular diseases, although weak to moderate, afteradjusting for the above mentioned potential confounding factors.

It still remains unclear whether periodontal diseases are causal forcardiovascular diseases. Clinicians should inform patients aboutthe association between periodontal and cardiovascular diseases,but should not overestimate or exaggerate the strength of thisrelationship.

RSUMObjet :Rsum et valuation critique des donnes probantes

actuellement disponibles concernant la puissance statistique et lanature (statistique et/ou causale) de lassociation entre les maladiesparodontales et cardiovasculaires. Mthodes :Lassociationstatistique entre les maladies parodontales et cardiovasculairesa t value la suite dune recherche dans PubMedet dans la

base de donnes de La Bibliothque Cochrane(CENTRALE), sur lesrevues systmatiques et les mta analyses en anglais, jusqu lafin du mois daot 2011; la possibilit de lassociation causale at examine en regard des critres de cause effet de BradfortHill. Rsultats et Discussion :Une association indpendante etstatistiquement significative, allant de faible modre, a ttrouve aprs rajustement des possibilits dues aux facteurs deconfusion : vieillissement, genre, race, tabagisme, hypertension,diabte, indicateurs dtat socioconomique, stress, obsit, diteriche en lipides et autres. Les analyses effectues dans cette tudeont dmontr que les critres de causalit de Bradford Hill taientpartiellement respects. Conclusions :Les maladies parodontalesont une association indpendante et statistiquement significativeavec les maladies cardiovasculaires, bien que faible modreaprs rajustement des possibilits dues aux facteurs de confusion

mentionns ci-dessus. Toutefois, on ne sait toujours pas trs bien siles maladies parodontales causent des maladies cardiovasculaires.Les cliniciens devraient informer les patients du rapport entre lesdeux maladies, mais sans surestimer la force de cette relation.

Key words:association; atherosclerosis; cardiovascular diseases; cause; evidence; periodontal diseases

INTRODUCTIONThroughout ancient history, Assyrians, Egyptians, Greeks,Romans and others pointed out that oral infectiousdiseases, such as periodontitis or dental caries, can affectsystemic health and disease.1,2During the last decade ofthe 19th century and the beginning of the 20th century,the so called focal infection theory was postulated onthe basis of publications and oral presentations providedby the American microbiologist, Willoughby DaytonMiller,3,4 and the British physician, William Hunter.5,6

According to this theory, microorganisms localized in aspecific area of the bodythe focus or nidus of infectionsuch as the oral tissues, or microorganism associatedproducts can be transmitted via the blood or lymphoidcirculation to other distant areas, such as extraoral tissues.This transmission subsequently causes various systemicconditionscardiovascular, pulmonary or gastric diseasesand others.2,7 During the first half of the 20th century,the focal infection theory was applied in dental clinicalpractice in an erroneous manner, including extractions of

E V I D E N C E F O R P R A C T I C E

THIS IS A PEER REVIEWED ARTICLE. Submitted 12 Oct. 2011; Revised 5 Mar. 2012; Accepted 13 Mar. 2012* Periodontist; Biomedical Research Foundation of the Academy of Athens, Academy of Athens, Athens, Greece. Perio C Dent, LLC., Douglasville, Georgia, USA.Correspondence to:Dr. Sotirios Kotsovilis; [email protected]
mailto:[email protected]:[email protected]


2/13

132 2012; 46, no.2: 131142

Kotsovilis and Slim

teeth to prevent or treat systemic diseases.1,2 The dogmaof massive extractions became obsolete throughout thesecond half of the twentieth century, and was no longerused in clinical practice.1,2This metamorphosis in theoryand clinical practice principally originated from theunderstanding that:

a) the causal factor of a systemic disease is notnecessarily an oral infection;2

b) the presence of an oral infection does not necessarilycause a systemic disease;2

c) the elimination of an oral infection (e.g., possiblyafter tooth extraction) does not necessarily reduceor eliminate a systemic disease;2and

d) the aim of dental treatment, and particularly ofperiodontal therapy, is the long term retention ofthe natural dentition in a biologically, functionally,aesthetically acceptable and symptom free state,avoiding the extraction of teeth as much aspossible.8,9

The association of oral infections with systemic

diseases has been extensively studied in the dental andmedical literature.2 Thus, dental and medical researchhave focused on the role of oral infections as risk factorsfor systemic diseases.2A risk factor can be defined as anexposure that increases the probability that disease willoccur.10In particular, the association between non surgicaldental procedures and bacteraemia11or subacute bacterialendocarditis12has been reported in the dental literatureat least since the 1960s. In the late 1980s and throughoutthe 1990s, a series of case control studies revealed asignificant independent association of poor dental healthto acute myocardial infarction after adjusting for manycardiovascular risk factors, such as age, smoking, diabetes,and hypertension.1316Dental health was assessed by a total

dental index, including the number of carious defects,missing teeth and periapical lesions, probing depths ofperiodontal pockets and the presence of pericoronitis.1316In another study, patients with a history of myocardialinfarction presented with a more severe periodontalcondition than subjects without such a history, andtherefore periodontal inflammation was associated with ahistory of myocardial infarction.17In the 1990s, it becameapparent that a novel branch of Periodontology ought tobe created, focusing on the theory and clinical practicerelated to the association between periodontal health ordisease and systemic health or disease; this new branchwas termed periodontal medicine.18

During the past two decades, the associationbetween periodontal and cardiovascular diseases hasbeen repeatedly evaluated using appropriate evidencebased methodologies, including the conduction ofseveral systematic reviews without meta analyses19,20 oraccompanied by meta analyses.2128

The objective of the present review was to summarizeand critically evaluate the available evidence, usingsystematic reviews and meta analyses, concerning thestatistical strength and the nature (statistical and/or causal)of the association between periodontal and cardiovasculardiseases.

Definition and basic description of periodontal andcardiovascular diseases

In the 1960s, classical clinical studies originallydocumented the theory that dental microbial plaque isthe pivotal aetiology factor for the initiation of gingivitis,inflammatory disease solely of the gingiva.2931 Overtime it was demonstrated both by animal studies32,33andepidemiological studies3437 that in certain situationsgingivitis could shift to periodontitis, particularly ifleft untreated or in individuals with poor oral hygiene.Periodontitis is an inflammatory disease of the periodontaltissues supporting the teethperiodontal ligament,alveolar bone or dental cementum.

It has been established that periodontitis is causedmainly by infection with Gram negative bacteria suchas Porphyromonas gingivalis, Tannerella forsythia, Prevotellaintermedia,Aggregatibacter actinomycetemcomitans,and Grampositive bacteria Peptostreptococcus micros, Streptococcusintermediusand others.38In periodontitis, the destruction ofperiodontal tissues supporting the teeth may be promoted

not only by microorganisms or their products, but alsoby the host response to the microbial challenge, involvingboth innate and adaptive immunity.39During the immune/inflammatory response, various host cellsneutrophils,monocytes, lymphocytes, fibroblasts and othersproduceproinflammatory mediators and cytokinesinterleukins(ILs), tumour necrosis factor (TNF), prostaglandin E2 andothersas well as proteolytic enzymes (proteinases), suchas matrix metalloproteinasescollagenases, gelatinasesand othersthat substantially contribute to periodontaldestruction.40,41

In this review, the term periodontal disease(s) is usedas a broad term for all inf lammatory pathological processesinvolving the periodontiumgingiva, periodontal

ligament, alveolar bone or dental cementum. It might benoted that although the term periodontal diseases hasbeen defined for use in clinical practice,42a definition ofthis term specifically for use in periodontal research stillremains open to discussion.43,44

In this review, the term cardiovascular disease(s) isused as a broad term for all conditions involving thecardiovascular systemconditions of the heart, thepericardium or the circulatory system. Thus, cardiovasculardiseases comprise atherosclerosis; atherosclerosis induceddiseases, such as coronary heart disease (myocardialischaemia, fatal or non fatal myocardial infarction)and peripheral vascular disease; infective endocarditis;thromboembolic events; cerebrovascular disease/accident(stroke); and other heart and vascular conditions.19,45

Atherosclerosis could be defined as a chronicinflammatory disease of the wall of large and mediumsized arteries, precipitated by increased levels ofcholesterol, predominantly of low density lipoproteins(LDL), in the blood.46,47 Atherosclerotic plaques maycomprise accumulated lipids, inflamed cellsleukocytes,arterial endothelial cells, arterial smooth muscle cells,lipid rich macrophages termed foam cells and othersnecrotic cores or regions of arterial calcification, and cancause narrowing of arteries that disturbs the physiologicalblood flow.46The main animal model of atherosclerosis is


3/13

2012; 46, no.2: 131142 133


the apolipoprotein E (apoE) deficient mouse model, whichwas introduced in 1992.48,49This mouse model may appearin two forms, involving either heterozygous mutant mice(apoE+/-mice) or homozygous mutant mice (apoE-/-mice).50

Can periodontal diseases have a statisticalassociation with cardiovascular diseases and what isthe strength of this association?

The systematic reviews available, without metaanalyses19,20 or with meta analyses,2128 demonstratedthat the majority of observational studiescohort, casecontrol and cross sectional studiesrevealed a statisticallysignificant positive association between periodontaland cardiovascular diseases, independent of traditionalcardiovascular risk factors, such as advancing age,gender, race, smoking, hypertension, diabetes, indicatorsof socioeconomic status, stress, obesity, and lipid richdiet. These traditional cardiovascular risk factors eitherhave been documented or still remain dubious afterthe conduction of a narrative review that specifically

addressed this issue in the Sixth European Workshop onPeriodontology in 2008.45The strength of this statisticalassociation could be regarded as weak to moderate. Table 1presents meta analyses2123,2527 that reported relative risk/odds ratio values (mean values [95% confidence intervals])and the corresponding strengths of association betweenperiodontal and cardiovascular diseases. A number ofstudies showed either no statistical association17,5153 orstatistically non significant trends toward a positiveassociation between periodontal and cardiovasculardiseases.5456

Can periodontal diseases have a causal associationwith cardiovascular diseases?

The evidence,1928 mentioned above, demonstratedthat periodontal diseases can increase the probabilitythat cardiovascular diseases will occur, irrespective of theeffect of potential confounders. Therefore, periodontaldiseases could be regarded as an independent risk factorfor the onset of cardiovascular diseases. The fact thatperiodontal diseases are able to increase the probabilityof cardiovascular diseases occuring does not necessarilyprove that periodontal diseases are also causative factorsfor the development of cardiovascular diseases. In 1965,the English epidemiologist Austin Bradford Hill proposedthe so called Hills criteria for causation, in an attempt todefine when a given factor is the cause or part of the causeof a disease (Table 2).2,57

Hills criteria for causation have already been usedto determine whether periodontal diseases might becausative factors for cardiovascular diseases.2An update ofthis analysis is presented below.

Criterion 1. Strength of the associationThe hypothesis stating that a causal association exists

between periodontal and cardiovascular diseases is notstrongly reinforced, as the strength of their associationcould be regarded as weak to moderate (mean relativerisk/odds ratio ranging from 1.1322 to 1.75;26 Table 1).Since periodontal diseases increase the probability that

cardiovascular diseases will occur by 13 percent (low value)to 75 percent (moderate value), it could be speculatedthat periodontal diseases alone, without the concomitantinfluence of other causal factors or risk factors, might notbe able to cause new events of cardiovascular diseases.Thus, the use of the first Hills criterion for causation alonecan neither prove nor disprove the presence of a causalassociation between periodontal and cardiovasculardiseases (Table 3).

Criterion 2. Consistency of the associationAs revealed by systematic reviews,1923,25,27 the majority

of existing studies generated similar results, highlightinga statistically significant positive association betweenperiodontal and cardiovascular diseases. Nevertheless,considering that a number of studies revealed either nostatistical association5153 or statistically non significanttrends toward a positive association between periodontaland cardiovascular diseases,54,55 it can be stated that theconsistency of the findings of available studies is notabsolute. Hence, the use of the second Hills criterionfor causation alone tends to support a causal associationbetween the two diseases, but does not provide irrefutableevidence (Table 3).

Meta analysis*Relative risk/odds ratio

Mean (95% CI)

Strength of

association

Janket et al.

2003211.19 (1.081.32) Weak

Khader et al.

2003221.13 (1.011.27) Weak

Meurman et al.

2004231.20 (1.081.32) Weak

Bahekar et al.

200725

Prospective cohort studies:

1.14 (1.071.21)

Case-control studies:

2.22 (1.593.12)Cross-sectional studies:

1.59 (1.331.91)

Weak

High

Moderate

Mustapha et al.200726

1.75 (1.322.34) Moderate

Humphrey et al.

200827

Periodontitis:1.24 (1.011.51)

Gingivitis:

1.35 (0.792.30)

Weak

Weak

CI: Confidence intervals

* Meta analyses are sequenced according to publication year;

meta analyses with the same publication year are sequenced

according to alphabetical order The strength of association between periodontal and

cardiovascular diseases was defined as weak when mean

relative risk/odds ratio was


4/13

134 2012; 46, no.2: 131142

Kotsovilis and Slim

Hills criterion for causation Description

1. Strength of the association

The stronger the association (as measured using appropriate statistical methods) between the suspected

aetiological factor and the specific effect (disease under investigation), the firmer the hypothesis becomes

that the nature of this association is causal.

2. Consistency of theassociation

The hypothesis of a causal association between the presumptive aetiological factor and the specific effect

or disease is s trengthened or supported when it is consistently and repeatedly reported in numerousstudies differing in various characteristics, such as populations, examiners, methods, circumstances, places,

and times.

3. Specificity of the

association

The speculation that the nature of the association is causal is strengthened or supported: if the suspected aetiological factor is reported to be associated only with the specific effect or disease

among various effects considered; or if the specific effect is reported to be associated only with the presumptive aetiological factor among

various suspected aetiological factors.

4. Temporal relationship

of the association

(temporality)

A necessary condition for a given factor to be the cause of a specific effect (disease) is that this factor must

always precede the onset of the specific effect.

5. Biological gradient (dose-response relationship)

If the frequency and/or the severity of a specific effect (disease) increases with the dose/degree/amount ofexposure to a suspected aetiological factor, a doseresponse relationship exists between the presumptiveaetiological factor and the specific effect. This strongly indicates the concomitant presence of a causal

association between the suspected aetiological factor and the specific effect.

6. Biological plausibility

The hypothesis of a causal association between the suspected aetiological factor and the specific effect

(disease) is strengthened: if the presumptive causal association appears to be consistent or compatible with accepted biological

knowledge; and if biological mechanisms can be documented by which the suspected aetiological factor could be able

to cause the specific effect.

7. CoherenceThe presumptive causal association between the suspected aetiological factor and the specific effect(disease) should not seriously conflict with currently established theory and knowledge in a specific field or

other related fields.

8. Experiment (experimental

evidence)

The hypothesis of a causal association between the suspected aetiological factor and the specific effect(disease) is substantially reinforced if the specific effect can be altered (reduced or prevented) as a result of

experimental interventions that affect (reduce or eliminate) the suspected aetiological factor.*

9. Analogy

In certain circumstances, the hypothesis of a causal association between the suspected aetiological factor

and the specific effect (disease) would possibly be strengthened if analogy existed with the effect of

another proven (true) aetiological factor or the proven (known) aetiology of another disease.

* More generally, this criterion could include the conduction of animal experiments in which the disease is experimentally reproduced after

exposure to the presumptive aetiological factor, as well as human intervention studies or trials in which appropriate intervention can

reduce or eliminate the disease.2

Table 2.Description of Bradford Hills criteria for causation.2,57

Criterion 3. Specificity of the associationAn independent statistically significant positive

association between periodontal and cardiovasculardiseases was evidenced above,1928 after adjusting fortraditional45 cardiovascular risk factors that are alsoassociated with periodontal diseases, such as advancingage, gender, race, smoking, hypertension, diabetes,indicators of socioeconomic status, stress, obesity, lipid-rich diet, and therefore can confound the associationbetween the two diseases.19,58 However, cardiovasculardiseases have a multifactorial aetiology; so the possibilityof residual confounding or incomplete control of potentialconfounding factors, due to incomplete statisticaladjustment, cannot be ruled out.58,59 Consequently, the

use of the third Hills criterion for causation alone tendsto strengthen the presumption of a causal associationbetween the two diseases, but does not provide proof(Table 3).

Criterion 4. Temporal relationship of the association(temporality)

Prospective cohort studies60,61 revealed that in anumber of study participants periodontal disease thathad been present at the study baseline was associatedwith new events of cardiovascular disease after baseline.In these study participants, cardiovascular disease wasnot present at baseline.60,61 Accordingly, it is clear thatthe suspected cause, periodontal disease, preceded the


5/13

2012; 46, no.2: 131142 135


effect, cardiovascular disease. It is important to note thatin these studies, adjustment for traditional cardiovascularrisk factors, such as age, gender, race, smoking, alcoholconsumption, systolic blood pressure, diabetes, education,poverty index, body mass index, cholesterol bloodlevels and physical activity, was made.60,61 The fourthHills criterion is crucial in establishing that periodontaldiseases can be:

a) a true risk factor rather than a putative risk factoras periodontal diseases would have been regardedhad the temporal sequence not been establishedby longitudinal studies, for example, if only crosssectional studies had been available;2

b) the cause of cardiovascular diseases.The presumption that an unknown or uncontrolled

causal factor, other than periodontal diseases, might havecaused cardiovascular diseases is plausible, taking intoaccount that cardiovascular diseases have a multifactorialaetiology. This hypothesis is substantially strengthened bythe fact that in the above mentioned prospective cohort

studies less than 20 percent of patients with periodontaldisease present at baseline did subsequently developnew events of cardiovascular diseases, whereas their vastmajority (more than 80%) did not develop cardiovasculardiseases.60,61Such statistical data tend to favour a non causalinterpretation of the association between periodontaland cardiovascular diseases. Consequently, the use of thefourth Hills criterion for causation alone substantiallystrengthens the hypothesis of a causal association betweenthe two diseases, but does not provide proof (Table 3).

Criterion 5. Biological gradient (doseresponse relationship)A doseresponse relationshipa biological gradient

between the severity or degree of the exposure and

occurrence of the effect or diseasebetween periodontaland cardiovascular diseases has been reported by individualstudies6164and confirmed by a meta analysis.26Increasingseverity of periodontal diseases resulted in highercumulative incidence of cardiovascular diseases afteradjusting for many potential confoundersincreasingage, gender, race, smoking, hypertension, diabetes, obesity,serum cholesterol, indicators of socioeconomic status andothers.19,58 In a number of studies,5153,55a doseresponserelationship was not found, suggesting that the fulfillmentof the fifth Hills criterion for causation is partial (Table 3).It is worth considering that the results of certain studiesmight not be directly comparable. In data analysis of theNational Health And Nutrition Examination Survey I(NHANES I),55 for example, periodontitis was defined onthe basis of the Russell Periodontal Index,65 whereas inthe data analysis of NHANES III,64a periodontal site wasdefined to exhibit periodontitis if probing pocket depth 3mm and also clinical attachment loss 3 mm were present.

Criterion 6. Biological plausibilityAccording to the sixth Hills criterion for causation,

the hypothesis of a causal association between thesuspected aetiology factor and the specific effect ordisease is strengthened if biological mechanisms canbe documented by which the suspected aetiology factor

could be able to cause the specific effect or disease (Table2). The available information on biological mechanismsthat might interpret the association between periodontaland cardiovascular diseases was reviewed.66Relying uponexisting information, it appears that periodontal diseasescould affect cardiovascular diseases either directly viamicrobial challenge, or indirectly via host response tomicrobial challengeimmune/inflammatory responseas described below.

The theory of a direct effect of periodontal diseaseson cardiovascular diseases via microbial challenge isessentially the focal infection theory;37 and thereforerefers to the transmission of periodontal pathogens, suchas P. gingivalis, from periodontal pockets to the bloodcirculation67and their ensuing invasion into atheroscleroticplaques.68 Reviews of animal and human studies havesummarized the evidence concerning the associationbetweenP. gingivalis infection and atherosclerosis.6971 Inhumans, fimbriae genotypes II and IV ofP. gingivaliswereidentified frequently in specimens of heart valves andatherosclerotic plaques (genotype II: 30.0%; and genotypeIV: 45.0%), as well as in dental plaque specimens (genotypeII: 35.7%; and genotype IV: 21.4%), suggesting a potentialrole of type II and IV clones ofP. gingivalisin cardiovasculardisease processes.72 The invasive P. gingivalis stain 381 isable to upregulate the expression of 68 genes, includingthose coding for the chemoattractant IL-8, endothelialcell adhesion molecules (intercellular adhesion molecule-1[ICAM-1], vascular cell adhesion molecule-1 [VCAM-1]and E- or P-selectin) and the proinflammatory mediatorsIL-6 and cyclooxygenase-2 in human aortic endothelialcells, as well as aortic tissues.73

P. gingivalisis also able tobind to Toll-like receptors (TLRs) -2 and -4 present on thesurface of endothelial cells, activate this type of cells thatsubsequently can promote the inflammatory mechanisms

Hills criterion for causation Degree of fulfillment

1. Strength of the association Partial fulfillment

2. Consistency of the association Partial fulfillment

3. Specificity of the association Partial fulfillment

4. Temporal relationship of the

association (temporality)Partial fulfillment

5. Biological gradient (dose-response

relationship)Partial fulfillment

6. Biological plausibility Complete fulfillment

7. Coherence Partial fulfillment

8. Experiment (experimental evidence) Partial fulfillment

9. Analogy Partial fulfillment

Table 3.Degree of fulfillment of Bradford Hills criteria for

causation, when evaluating the potential for a causal association

between periodontal and cardiovascular diseases.


6/13

136 2012; 46, no.2: 131142

Kotsovilis and Slim

implicated in the early stages of atherosclerosis.74Studies inapoE deficient mice, either homozygous (apoE-/-mice)73,75orheterozygous (apoE+/-mice),76,77documented that systemicinflammation induced by oral infection withP. gingivaliscould be able to accelerate and intensify in severity, butclearly not initiate, the formation of atherosclerotic lesionsand the progression of atherosclerosis. Apart from mice,

P. gingivalis has been reported to affect the progressionof atherosclerosis in other animals as well, such as pigs78and rabbits.79 Oral infection with putative periodontalpathogens other than P. gingivalis, such as T. forsythia,80Treponema denticola,80 or A. actinomycetemcomitans,81 hasbeen also associated with the progression of atherosclerosisin apoE-/-mice.

An additional theory of an indirect effect of periodontaldiseases on cardiovascular diseases via host response tomicrobial challengeimmune/inflammatory responsehas also been supported by experimental findings.28,61,82According to this theory, host response to microbialchallenge during the progression of periodontal diseases

involves the production of acute phase proteins byvascular endothelial cells, such as C-reactive protein(CRP), plasminogen activator-1 and fibrinogen.82 Acutephase proteins are proinflammatory mediators producedduring host response to tissue trauma, inflammation,infection or malignant neoplasia, which are able to inhibitmicrobial pathogens, to activate complement factors andto promote tissue regeneration or repair.28 The serumlevel of CRP is markedly increased up to 10,000 timesin response to inflammation. Consequently, serum CRPconcentration is considered to be a biochemical markerof systemic inflammation and/or tissue catastrophe thatmight progress in infectious diseasesbacterial, fungal orviraland inflammatory or autoimmune diseases, such

as rheumatoid arthritis, psoriatic arthritis, Crohn disease,and other conditions.83After controlling the heterogeneityamong cross sectional studies, a meta analysis revealedthat patients with periodontitis present statistically highlysignificantly greater serum CRP concentrations thanthose of periodontally healthy individuals.28Since CRP isconsidered to be a marker of systemic inflammation,83 itcan be deduced that periodontitis can promote a systemicinflammation. CRP can also facilitate the transformationof macrophages into foam cellslipid rich macrophagesin atherosclerotic plaques, a hallmark of the early stagesof atherosclerosis.66Furthermore, other proinflammatorymediators are produced:

a) by gingival epithelial cells, for example, IL-1,prostaglandin E2 and TNF-, or

b) by vascular endothelial cells, for example,intercellular adhesion molecules, vascular celladhesion molecules and P- or E-selectin.66

These inflammatory mediators can also enter bloodcirculation and promote inflammatory reactions, andsubsequently the formation of atherosclerotic plaques.66

In the mid 1990s, the concept of hyperinflammatoryphenotype was introduced.61 Patients with thehyperinflammatory phenotype exhibit an abnormallyincreased host response to periodontal bacteria orbacterial antigens, inducing the release of up to ten times

higher quantities of proinflammatory mediatorsIL-1,prostaglandin E2 and TNF-and othersby monocytes.61These proinflammatory mediators can locally promoteperiodontal destruction and systemically increase therisk for the development of cardiovascular diseases.61The validity of the concept of hyperinflammatoryphenotype may be supported by the observation thatcertain individuals, presumed to present this monocytephenotype, exhibit markedly more intense host responseto periodontal bacterial challenge. Consequently, theyare more susceptible to periodontal diseases than otherindividuals who do not exhibit a hyperinflammatoryphenotype.39

In synopsis, ample experimental evidence has beenaccumulated about various biological mechanismsthrough which periodontal diseases might causecardiovascular diseases. It might be stressed that thisexperimental evidence proves the biological plausibilityof a causal association between the two diseases, but byno means proves a causal association between the two

pathological entities (Table 3).

Criterion 7. CoherenceThis review, particularly the mechanisms mentioned

in the previous section, generally indicates that apotential causal association between periodontal andcardiovascular diseases does not conflict with currentlyestablished theory and scientific knowledge in the fields ofPeriodontology, Cardiology, Biology or other related fields.The use of the seventh Hills criterion for causation aloneindicates that a causal association between periodontaland cardiovascular diseases is merely feasible or plausible,but is not a proven fact (Table 3).

Criterion 8. Experiment (experimental evidence)The experimental evidence concerning a suspected

causal association between the two diseases can be derivedboth from animal and human studies. Animal studies werepreviously mentioned in the sixth criterion of this review.Human studies, either observational or interventionstudies, constitute the second source of experimentalevidence concerning the suspected causal associationbetween periodontal and cardiovascular diseases.

An observational study could be defined as a studyin which the investigators do not seek to intervene, butsimply observe the course of events.84The evidence derivedfrom observational studies was previously reviewed withrespect to Hills criteria for causation 1, 2, 4 and 5.

An intervention study or trial might be defined as anexperiment designed to investigate the effect of a particularhealthcare intervention or to compare the effects of twoor more healthcare interventions.84 Intervention studiesor trials can include uncontrolled trials, non randomizedcontrolled trials and randomized controlled trials.84Theevidence originating from intervention studies has beenreviewed.59In intervention studies aimed at investigatingthe suspected causal association between periodontal andcardiovascular diseases, periodontal therapy is applied toreduce in severity or to eliminate the existing periodontaldisease, which is the suspected cause or exposure.58


7/13

2012; 46, no.2: 131142 137


Subsequently, it is evaluated whether the existingcardiovascular disease, which is the effect, will also bereduced in severity or be eliminated.59 If cardiovasculardisease is reduced in severity or is eliminated, a causalassociation between periodontal and cardiovasculardisease appears to exist.59A meta analysis of interventionstudies published up to 1 June 2007 revealed that plasmaCRP levels were statistically significantly reduced afternon surgical periodontal therapy, compared with pre-treatment levels.28However, an earlier meta analysis hadrevealed no statistically significant effect of periodontaltherapy on CRP levels.24 The discrepancy in the resultsof these two meta analyses24,28 could be explained bythe limited number of existing trials and by the lowtotal number of subjects included in the meta analyses.Certain randomized controlled trials published afterJune 2007 revealed a statistically significant reduction inserum CRP levels following periodontal therapy.8587Otherrandomized controlled trials demonstrated statisticallynon significant alterations in serum CRP levels after

periodontal therapy.88,89

In a pilot multicenter randomizedcontrolled trial, Periodontitis and Vascular Events (PAVE)study,89non surgical and/or surgical periodontal therapywas applied in patients having already undergone a firstepisode of cardiovascular disease. Treatment was efficaciousin statistically significantly reducing mean probing pocketdepth at six months, compared with baseline, but failedto statistically significantly reduce mean levels of serumCRP or gingival crevicular fluid IL-1.89It is of interest tonote that the mean probing pocket depth was reducedfrom 2.69 mm (with standard deviation: 0.06 mm) atbaseline to 2.41 mm (with standard deviation: 0.06 mm)at six months.89Thus, at six months periodontal therapyresulted in a mean reduction in probing pocket depth of

0.28 mm.89The outcome of periodontal therapy could beregarded as clinically limited. This interpretation of theclinical therapeutic outcome appears to be consistentwith the absence of statistical significance in the effect ofperiodontal therapy on serum biochemical parameters.

Apart from the effect of periodontal therapy on serumCRP levels, data concerning the impact of periodontaltherapy on other markers implicated in cardiovasculardiseases are also available in the literature. For example,in an intervention study,90 non surgical and surgicaltreatments of severe periodontitis that resulted in astatistically significant reduction in probing pocket depthalso induced a statistically significant decrease in plasmaconcentration of LDL, haptoglobin, IL-18 and interferon-,as well as a statistically significant increase in plasmaconcentration of HDL at 12 months post treatment.90Thesefindings indicated that the combination of non surgicaland surgical periodontal therapy of severe periodontitiscan systemically affect many biochemical risk markers foratherosclerosis.90

Other studies have reported that non surgical treatmentof moderate to severe periodontitis can improve thelevels of the dysfunction of the vascular endotheliummeasured as flow mediated dilatation of the brachialarteryregarded as the first inflammatory alteration inthe process of early atherosclerosis.47,9193Potential causes

of atherosclerosis associated endothelial dysfunctionmight include increased LDL and/or modified high plasmaconcentrations of homocysteine, microorganismssuchas Chlamydia pneumoniaeor herpes virusesfree radicalsproduced owing to smoking, diabetes or hypertensionand other factors.47Collectively, these studies9193tend tosuggest that periodontal therapy can affect biomarkersof both systemic inflammation and endothelialdysfunctionthe first phenomenon in the inflammatoryatherosclerotic processas surrogate outcome measures59,94for cardiovascular diseases.

Overall, in accordance with the Consensus Reportof the Sixth European Workshop on Periodontology,95existing data indicate that the presence of periodontitiscontributes to the total burden of infection orinflammation and, in susceptible individuals, could alsocontribute to cardiovascular events and cerebrovascularaccidents. Further research is required to determine theeffect of periodontal treatment on these aforementionedconditions.95

Despite the presence of intervention studies concerningthe effect of periodontal therapy on surrogate outcomemeasures for cardiovascular diseases, additional trialsdesigned to determine whether periodontal therapycan affect more definitive outcome measures forcardiovascular condition are required to draw definitiveconclusions. Definitive outcome measures could includecardiovascular events, admissions to hospital or deathsdue to cardiovascular conditions.94

Until long term trials with large sample sizes anddefinitive outcome measures for cardiovascular diseasesare published in the literature demonstrating that nonsurgical and/or surgical periodontal therapy can eliminatecardiovascular diseases, the fulfillment of the eighth Hills

criterion for causation (experiment) might be regarded aspartial (Table 3).

Criterion 9. AnalogyThe association between periodontal and cardiovascular

diseases presents analogiesfor example, similarpathogenic mechanismswith:

a) the association between periodontal diseases andother systemic conditions, such as diabetes,2,9698preterm and/or low weight births,2,19 or respiratoryinfections,2,99or

b) the association between other systemic conditionsthat can interfere with chronic inflammationsuchas diabetes97and cardiovascular diseases.

However, even though these pathological entitieshave been associated with each other statistically and/orbiologically, a causal association has not been demonstratedin the above mentioned cases. Consequently, the useof the ninth Hills criterion for causation alone appearsto provide unclear information about a potential causalassociation between periodontal and cardiovasculardiseases (Table 3).

In synopsis, as shown in Table 3, the analysis performedin this review demonstrated that Bradford Hills criteriafor causation were partially fulfilled, with the possibleexception of the sixth criterionbiological plausibility.


8/13

138 2012; 46, no.2: 131142

Kotsovilis and Slim

Can periodontal diseases have a non causalassociation with cardiovascular diseases?

On the basis of the finding that Hills criteria forcausation were partially fulfilled in the present analysis,it still remains questionable whether periodontal diseasesare causal for cardiovascular diseases. Thus, the statisticalassociation between the two diseases may not necessarilybe a causal associationeither direct or indirect, forexample, by an intervening variablebut could also havea non causal nature.

The traditional dictum correlation does notimply causation was based mainly upon the theoriespostulated by Francis Galton and Karl Pearson.100,101 In1889, after examining forearm and height measurements,Francis Galton introduced the statistical concept ofcorrelation.100 Karl Pearson, who was Galtons student,subsequently introduced both the Pearsons correlationtest and the concept of a spurious correlation.101 InEldertons Pearsonian textbook,102 it was defined, itis possible to obtain a significant value for a coefficient

of correlation when in reality the two functions areabsolutely uncorrelated. Such a result is called spuriouscorrelation.

In light of these statistical concepts and theories, itbecomes clear that:

a) a statistical association between two variables isa necessary, but not sufficient, condition for aconcomitant causal association, and

b) a statistical association merely provides indications,but not proof, of a causal association.

The issue that subsequently arises could be stated asfollows: if the statistical association between periodontaland cardiovascular diseases has a non causalspuriousnature, then under which circumstances is this non causal

statistical association anticipated to occur? The answer isthat a spurious correlation or association between the twodiseases could be statistical whereby the two pathologicalentities have no causal association, but are statisticallyassociated in one of the following manners:

a) incidently, because no statistical test can entirelyexclude the role of chance;

b) coincidently, because periodontal diseases mightchronically precede cardiovascular diseases, withoutbeing the cause of cardiovascular diseases.

The cause might be other, unknown or uncontrolledfactors; these factors might also be able to causeperiodontal diseases, and therefore be termed confoundingfactors, or they might be non causally associated withperiodontal diseases. In many studies, the possibility ofresidual confounding or incomplete control of potentialconfounding factors, owing to incomplete statisticaladjustment, cannot be ruled out.58,59

In light of these considerations, the interpretation of anon causal association between the two diseases appearsto be plausible. Relying upon existing literature data, itis equivocal whether periodontal diseases are causally ornon causally associated with cardiovascular diseases.

DISCUSSIONThis review summarized and critically evaluated theavailable evidence using systematic reviews and metaanalyses concerning the statistical strength and thecausal or non causal nature of the association betweenperiodontal and cardiovascular diseases.

The existing systematic reviewswithout metaanalyses19,20or with meta analyses2128revealed that themajority of observational studies tended to demonstratea statistically significant positive association betweenthe two diseases, independent of traditionaleitherdocumented or still dubious as specifically reviewed45cardiovascular risk factors. The strength of this statisticalassociation could be regarded as weak to moderate (Table1). Significant concerns with respect to these findings are:

a) whether the reported statistically significant positiveassociations are real associations, or

b) whether they are caused by residual confounding byrisk factors, such as smoking, common in periodontaland cardiovascular diseases, or

c) whether they are caused by incomplete control ofpotential confounding factors owing to incompletestatistical adjustment.58,59

After demonstrating the presence of a statisticalassociation between the two diseases, a deeper and moredetailed level of analysis in this review involved assessingwhether periodontal diseases might be causative factorsfor cardiovascular diseases. The biological plausibility of acausal association between periodontal and cardiovasculardiseases appears to have sufficient experimental evidencemainly based on animal studies using the apoE-deficientmouse model of atherosclerosis.73,7577 Prospectivecohort studies60,61 revealed that in a number of studyparticipants, periodontal disease that had been present

at the study baseline was associated with new events ofcardiovascular disease after baseline. However, the factthat only the minority (less than 20%) of patients withperiodontal diseases at baseline subsequently developedcardiovascular diseases,60,61 tends to favour a non causalinterpretation of the association between the two diseases.In such cases, it is a requisite to additionally perform ahealthcare intervention aimed at reducing or eliminatingthe suspected cause, provided that the disease state is notirreversible, in which case an intervention strategy wouldnot be meaningful. If the reduction or elimination of thesuspected cause results in a reduction or elimination of thedisease, then the suspected cause is a true aetiology factorfor the disease, provided that no other factor has affectedthe observed outcome, often practically too difficult orimpossible to ensure.

The classical clinical studies performed by the researchteam of Le et al.29,30demonstrated that dental microbialplaque is the cause of gingivitis. The studies serve as acharacteristic example for the methodology that includesprospective follow up, and then intervention thataffects the suspected cause of an effect or disease.29,30 Inthese studies, bacterial accumulation on teeth inducedinflammation in related gingival tissues and subsequentplaque removal resulted in the resolution of the clinicalsigns of gingival inflammation.29,30


9/13

2012; 46, no.2: 131142 139


In the case of the suspected causal association betweenperiodontal and cardiovascular diseases, interventionstudies or trials reporting on the effect of non surgicaland/or surgical periodontal therapy upon definitiveoutcome measures for cardiovascular conditioncardiovascular events, admissions to hospital or deathsdue to cardiovascular reasons94are not available. Existingtrials have included only surrogate outcome measuresfor cardiovascular diseasesbiomarkers of systemicinflammation and/or endothelial dysfunction.47,9193Thus,evidence for a causal association between periodontal andcardiovascular diseases is incomplete. It is recommendedthat intervention studies examining the effect ofperiodontal therapy on cardiovascular condition includelarge sample sizes to allow for statistical analyses ofadequate statistical power, as well as long term follow upperiods to record definitive cardiovascular endpoints.94

These methods are appropriate for use in a single study,but in the modern era of scientific evidence, a populationof studies rather than a single study will be required for

a documentation of a causal association. For this reason,additional criteria for defining a causal association arenecessary for use in a population of studies. In orderto address this issue, Hills criteria for causation wereemployed in the present review. The use of Hills criteriafor causation is an established method to examine thepresence of a causal association between a suspected causeand an effect (disease); these criteria are widely used insystematic and non systematic reviews assessing causationin the medical and dental literature.103,104 Using Hillscriteria for causation, the analysis performed in the presentreview demonstrated that despite the wide plethora ofdata accumulated throughout the 2000s, it still remainsuncertain whether or not periodontal diseases have a

causal association with cardiovascular diseases.After showing that a causal association between the two

diseases cannot be proven on the basis of existing data, afair, non biased approach necessitated the examinationof the possibility of a non causal association between thetwo diseases. According to the latter concept, periodontaland cardiovascular diseases could be statistically, butnon causally, associated by chance or by coincidence, ifperiodontal diseases chronically precede cardiovasculardiseases, without being the cause of cardiovasculardiseases, whereas the cause could be other unknown oruncontrolled factorsconfounding factors or factors noncausally associated with periodontal diseases.

Collectively, it appears uncertain whether theinterpretation of a non causal association might bepreferred over the interpretation of a causal associationbetween the two diseases.

Finally, with respect to the applicability of theevidence, clinicians should inform patients that researchhas documented the presence of a positive statisticalassociation between periodontal and cardiovasculardiseases. Clinicians might also consider mentioningthat the strength of this statistical association is weakto moderate, but certainly not strong, and therefore thestrength of this relationship should not be overestimatedor overemphasized. Recommendations for dental clinical

practice were published in a consensus report of theeditors of The American Journal of Cardiology and Journalof Periodontology.105 Depending on each patient, theserecommendations might mainly include:

patient information about the association betweenperiodontal and cardiovascular diseases;

medical evaluation of the patient, if considerednecessary in the presence of major cardiovascular riskfactors, past cardiovascular events or familial historyof such risk factors/events;

risk factor treatment, which might compriseweight loss, physical activity, reduced intake ofsaturated or trans fats, moderation of alcoholintake, pharmacological therapy, discontinuationof smoking, treatment of hypertension, metabolicsyndrome and other risk factors;

periodontal or other dental therapy; and eventually, close cooperation between the periodontist/dentist

and the physician.105

CONCLUSIONSWithin the limits of this review, the following conclusionsmay be drawn. Evidence documents that periodontaldiseases have an independent statistically significantassociation with cardiovascular diseases, although weakto moderate, after adjusting for potential confoundingfactors, such as advancing age, gender, race, smoking,hypertension, diabetes, indicators of socioeconomic status,stress, obesity, lipid rich diet and others. However, thepresent analysis demonstrates only a partial fulfillmentof Bradford Hills criteria for causation, at least in light ofavailable evidence. In this respect, it still remains doubtfulwhether periodontal diseases are causal for cardiovasculardiseases. Additional studies are required for the resolution

of this complex issue.

Conflict of interest statement: No conflicts ofinterest exist between study authors, and no fundingwas used for the present study.

REFERENCES

1. OReilly PG, Claffey NM. A history of oral sepsis as a cause ofdisease. Periodontol 2000.2000;23:1318.

2. Williams RC, Paquette D. Periodontitis as a risk for systemicdisease. In: Lindhe J, Karring T, Lang NP, editors. ClinicalPeriodontology and Implant Dentistry. 4th edition. Copenhagen:Blackwell Munksgaard, Blackwell Publishing Ltd. 2003;36686.

3. Miller WD. The micro-organisms of the human mouth: the localand general diseases which are caused by them. Philadephia: SSWhite. 1880;274342.

4. Miller WD. The human mouth as a focus of infection. DentalCosmos.1891;33:689713.

5. Hunter W. Oral sepsis as a cause of disease. Br Med J.1900;2:21516.

6. Hunter W. An address on the role of sepsis and antisepsis inmedicine. Lancet.1911;1:7986.

7. Pallasch TJ, Wahl MJ. Focal infection: new age or ancienthistory? Endodontic Topics.2003;4:3245.


10/13

140 2012; 46, no.2: 131142

Kotsovilis and Slim

8. Greenwell H. Committee on Research, Science and Therapy.American Academy of Periodontology. Position paper: guidelinesfor periodontal therapy.J Periodontol.2001;72:1624628.

9. Graetz C, Drfer CE, Kahl M, Kocher T, Fawzy El-Sayed K, WiebeJF, Gomer K, Rhling A. Retention of questionable and hopelessteeth in compliant patients treated for aggressive periodontitis.

J Clin Periodontol.2011;38:70714.

10. Beck JD. Methods of assessing risk for periodontitis

and developing multifactorial models. J Periodontol.1994;65(Suppl.5):46878.

11. Conner HD, Haberman S, Collings CK, Winford TE. Bacteremiasfollowing periodontal scaling in patients with healthy appearinggingiva.J Periodontol.1967;38:46672.

12. Eisenbud L. Subacute bacterial endocarditis precipitated bynonsurgical dental procedures. Report of two cases. Oral SurgOral Med Oral Pathol.1962;15:62427.

13. Mattila KJ, Nieminen MS, Valtonen VV, Rasi VP, KesniemiYA, Syrjl SL, Jungell PS, Isoluoma M, Hietaniemi K, JokinenMJ. Association between dental health and acute myocardialinfarction. BMJ.1989;298:77981.

14. Mattila KJ, Valle MS, Nieminen MS, Valtonen VV, Hietaniemi KL.Dental infections and coronary atherosclerosis. Atherosclerosis.1993;103:20511.

15. Mattila KJ, Valtonen VV, Nieminen M, Huttunen JK. Dentalinfection and the risk of new coronary events: prospectivestudy of patients with documented coronary artery disease.Clin Infect Dis.1995;20:58892.

16. Mattila KJ, Asikainen S, Wolf J, Jousimies-Somer H, ValtonenV, Nieminen M. Age, dental infections, and coronary heartdisease.J Dent Res.2000;79:75660.

17. Simonka M, Skaleric U, Hojs D. Condition of teeth andperiodontal tissue in patients who had suffered a heart attack.Zobozdrav Vestn.1988;43:8183.

18. Williams RC, Offenbacher S. Periodontal medicine: theemergence of a new branch of periodontology. Periodontol2000.2000;23:912.

19. Madianos PN, Bobetsis GA, Kinane DF. Is periodontitisassociated with an increased risk of coronary heart diseaseand preterm and/or low birth weight births?J Clin Periodontol.

2002;29(Suppl.3):2236.20. Scannapieco FA, Bush RB, Paju S. Associations betweenperiodontal disease and risk for atherosclerosis, cardiovasculardisease, and stroke. A systematic review. Ann Periodontol.2003;8:3853.

21. Janket SJ, Baird AE, Chuang SK, Jones JA. Meta-analysis ofperiodontal disease and risk of coronary heart disease andstroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod.2003;95:55969.

22. Khader Y, Albashaireh Z, Alomari MA. Periodontal diseasesand the risk for coronary heart and cerebrovascular diseases: ameta-analysis.J Periodontol.2003;75:1046053.

23. Meurman JH, Sanz M, Janket SJ. Oral health, atherosclerosis, andcardiovascular disease. Crit Rev Oral Biol Med.2004;15:40313.

24. Ioannidou E, Malekzadeh T, Dongari-Bagtzoglou A. Effectof periodontal treatment on serum C-reactive protein

levels: a systematic review and meta-analysis. J Periodontol.2006;77:1635642.

25. Bahekar AA, Singh S, Saha S, Molnar J, Arora R. The prevalenceand incidence of coronary heart disease is significantly increasedin periodontitis: a meta-analysis. Am Heart J.2007;154:83037.

26. Mustapha IZ, Debrey S, Oladubu M, Ugarte R. Markersof systemic bacterial exposure in periodontal disease andcardiovascular disease risk: a systematic review and meta-analysis.J Periodontol.2007;78:2289302.

27. Humphrey LL, Fu R, Buckley DI, Freeman M, Helfand M.Periodontal disease and coronary heart disease incidence:a systematic review and meta-analysis. J Gen Intern Med.2008;23:2079086.

28. Paraskevas S, Huizinga JD, Loos BG. A systematic review andmeta-analyses on C-reactive protein in relation to periodontitis.

J Clin Periodontol.2008;35:27790.

29. Le H, Theilade E, Jensen SB. Experimental gingivitis in man.JPeriodontol.1965;36:17787.

30. Theilade E, Wright WH, Jensen SB, Le H. Experimentalgingivitis in man. II. A longitudinal clinical and bacteriologicalinvestigation.J Periodontal Res.1966;1:113.

31. Le H, Theilade E, Jensen SB, Schiott CR. Experimental gingivitisin man. III. The influence of antibiotics on gingival plaquedevelopment.J Periodontal Res.1967;2:28289.

32. Saxe SR, Greene JC, Bohannan HM, Vermillion JR. Oral debris,calculus and periodontal disease in the beagle dog. Periodontics1967;5:21724.

33. Lindhe J, Hamp SE, Le H. Plaque-induced periodontal diseasein beagle dogs. A 4-year clinical, roentgenographical andhistometric study.J Periodontal Res.1975;10:24355.

34. Le H, Anerud A, Boysen H, Smith MR. The natural history ofperiodontal disease in man. Study design and baseline data.JPeriodontal Res.1978;13:55062.

35. Le H, Anerud A, Boysen H, Smith MR. The natural history ofperiodontal disease in man. Tooth mortality rates before 40

years of age.J Periodontal Res.1978;13:56372.

36. Le H, Anerud A, Boysen H, Smith MR. The natural history ofperiodontal disease in man. The rate of periodontal destructionbefore 40 years of age.J Periodontol.1978;49:60720.

37. Le H, Anerud A, Boysen H, Morrison E. Natural history ofperiodontal disease in man. Rapid, moderate and no loss ofattachment in Sri Lankan laborers 14 to 46 years of age.J ClinPeriodontol.1986;13:43140.

38. Socransky SS, Haffajee AD, Cugini MA, Smith C, Kent RL Jr.Microbial complexes in subgingival plaque. J Clin Periodontol.1998;25:13444.

39. Offenbacher S. Periodontal diseases: pathogenesis. AnnPeriodontol.1996;1:82178.

40. Preshaw PM, Hefti AF, Jepsen S, Etienne D, Walker C, BradshawMH. Subantimicrobial dose doxycycline as adjunctive treatmentfor periodontitis. A review.J Clin Periodontol.2004;31:697707.

41. Sorsa T, Uitto VJ, Suomalainen K, Vauhkonen M, Lindy S.

Comparison of interstitial collagenases from human gingiva,sulcular fluid and polymorphonuclear leukocytes.J PeriodontalRes.1988;23:38693.

42. Armitage GC. Development of a classification systemfor periodontal diseases and conditions. Ann Periodontol.1999;4:16.

43. Preshaw PM. Definit ions of periodontal disease in research. JClin Periodontol.2009;36:12.

44. Savage A, Eaton KA, Moles DR, Needleman I. A systematic reviewof definitions of periodontitis and methods that have been usedto identify this disease.J Clin Periodontol.2009;36:45867.

45. Persson GR, Persson RE. Cardiovascular disease andperiodontitis: an update on the associations and risk. J ClinPeriodontol.2008;35(Suppl.8):36279.

46. Galkina E, Ley K. Immune and inflammatory mechanisms ofatherosclerosis. Annu Rev Immunol.2009;27:16597.

47. Ross R. Atherosclerosis -an inflammatory disease.N Engl J Med.1999;340:11526.

48. Piedrahita JA, Zhang SH, Hagaman JR, Oliver PM, Maeda N.Generation of mice carrying a mutant apolipoprotein E geneinactivated by gene targeting in embryonic stem cells. Proc NatlAcad Sci U S A.1992;89:4471475.

49. Plump AS, Smith JD, Hayek T, Aalto-Setl K, Walsh A, VerstuyftJG, Rubin EM, Breslow JL. Severe hypercholesterolemia andatherosclerosis in apolipoprotein E-deficient mice created byhomologous recombination in ES cells. Cell.1992;71:34353.

50. JawieJ, Nastalek P, Korbut R. Mouse models of experimentalatherosclerosis.J Physiol Pharmacol.2004;55:50317.


11/13

2012; 46, no.2: 131142 141


51. Howell TH, Ridker PM, Ajani UA, Hennekens CH, Christen WG.Periodontal disease and risk of subsequent cardiovascular diseasein U.S. male physicians.J Am Coll Cardiol.2001;37:44550.

52. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA. Examiningthe link between coronary heart disease and the elimination ofchronic dental infections.J Am Dent Assoc.2001;132:88389.

53. Tuominen R, Reunanen A, Paunio M, Paunio I, Aromaa A. Oralhealth indicators poorly predict coronary heart disease deaths.

J Dent Res.2003;82:71318.54. Joshipura KJ, Rimm EB, Douglass CW, Trichopoulos D, Ascherio

A, Willett WC. Poor oral health and conorary heart disease. JDent Res.1996;75:1631636.

55. Hujoel PP, Drangsholt M, Spiekerman C, DeRouen TA.Periodontal disease and coronary heart disease risk. JAMA.2000;284:1406410.

56. Jansson L, Lavstedt S, Frithiof L, Theobald H. Relationshipbetween oral health and mortality in cardiovascular diseases.JClin Periodontol.2001;28:76268.

57. Hill AB. The environment and disease: association or causation?Proc R Soc Med.1965;58:295300.

58. Beck JD, Offenbacher S. The association between periodontaldiseases and cardiovascular diseases: a state-of-the-sciencereview. Ann Periodontol. 2001;6:915.

59. Tonetti MS. Periodontitis and risk for atherosclerosis: an updateon intervention trials.J Clin Periodontol.2009;36(Suppl.10):1519.

60. DeStefano F, Anda RF, Kahn HS, Williamson DF, Russel l CM.Dental disease and risk of coronary heart disease and mortality.BMJ.1993;306:68891.

61. Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S.Periodontal disease and cardiovascular disease. J Periodontol.1996;67(Suppl.10):1123137.

62. Beck JD, Offenbacher S, Williams R, Gibbs P, Garcia R.Periodontitis: a risk factor for coronary heart disease? AnnPeriodontol.1998;3:12741.

63. Beck JD, Elter JR, Heiss G, Couper D, Mauriello SM, OffenbacherS. Relationship of periodontal disease to carotid artery intima-media wall thickness: the atherosclerosis risk in communities(ARIC) study. Arterioscler Thromb Vasc Biol.2001;21:1816822.

64. Arbes SJ Jr, Slade GD, Beck JD. Association between extent

of periodontal attachment loss and self-reported historyof heart attack: an analysis of NHANES III data. J Dent Res.1999;78:1777782.

65. Russell AL. A system of classification and scoring for prevalencesurveys of periodontal disease.J Dent Res.1956;35:35059.

66. Huck O, Saadi-Thiers K, Tenenbaum H, Davideau JL, RomagnaC, Laurent Y, Cottin Y, Roul JG. Evaluating periodontal riskfor patients at risk of or suffering from atherosclerosis: recentbiological hypotheses and therapeutic consequences. ArchCardiovasc Dis.2011;104:35258.

67. Hu SW, Huang CH, Huang HC, Lai YY, Lin YY. Transvasculardissemination of Porphyromonas gingivalis from a sequesteredsite is dependent upon activation of the kallikrein/kinin pathway.

J Periodontal Res.2006;41:20007.

68. Haraszthy VI, Zambon JJ, Trevisan M, Zeid M, Genco RJ.Identification of periodontal pathogens in atheromatous

plaques.J Periodontol.2000;71:1554560.69. Gibson FC 3rd, Yumoto H, Takahashi Y, Chou HH, Genco

CA. Innate immune signaling and Porphyromonas gingivalis-accelerated atherosclerosis.J Dent Res.2006;85:10621.

70. Gibson FC 3rd, Genco CA. Porphyromonas gingivalis mediatedperiodontal disease and atherosclerosis: disparate diseases withcommonalities in pathogenesis through TLRs. Curr Pharm Des.2007;13:3665675.

71. Hayashi C, Gudino CV, Gibson FC 3rd, Genco CA. Review:Pathogen-induced inflammation at sites distant from oralinfection: bacterial persistence and induction of cell-specificinnate immune inflammatory pathways. Mol Oral Microbiol.2010;25:30516.

72. Nakano K, Inaba H, Nomura R, Nemoto H, Takeuchi H, YoshiokaH, Toda K, Taniguchi K, Amano A, Ooshima T. Distribution ofPorphyromonas gingivalis fimA genotypes in cardiovascularspecimens from Japanese patients. Oral Microbiol Immunol.2008;23:17072.

73. Chou HH, Yumoto H, Davey M, Takahashi Y, Miyamoto T,Gibson FC 3rd, Genco CA. Porphyromonas gingivalis fimbria-dependent activation of inflammatory genes in human aortic

endothelial cells. Infect Immun.2005;73:5367378.74. Argueta JG, Shiota S, Yamaguchi N, Masuhiro Y, Hanazawa

S. Induction of Porphyromonas gingivalis GroEL signaling viabinding to Toll-like receptors 2 and 4.Oral Microbiol Immunol.2006;21:24551.

75. Lalla E, Lamster IB, Hofmann MA, Bucciarelli L, Jerud AP,Tucker S, Lu Y, Papapanou PN, Schmidt AM. Oral infectionwith a periodontal pathogen accelerates early atherosclerosisin apolipoprotein E-null mice. Arterioscler Thromb Vasc Biol.2003;23:1405411.

76. Li L, Messas E, Batista EL Jr, Levine RA, Amar S. Porphyromonasgingivalis infection accelerates the progression of atherosclerosisin a heterozygous apolipoprotein E-deficient murine model.Circulation. 2002;105:86167.

77. Amar S, Wu SC, Madan M. Is Porphyromonas gingival is cellinvasion required for atherogenesis? Pharmacotherapeutic

implications.J Immunol.2009;182:1584592.78. Brodala N, Merricks EP, Bellinger DA, Damrongsri D,

Offenbacher S, Beck J, Madianos P, Sotres D, Chang YL, KochG, Nichols TC. Porphyromonas gingivalis bacteremia inducescoronary and aortic atherosclerosis in normocholesterolemicand hypercholesterolemic pigs. Arterioscler Thromb Vasc Biol.2005;25:1446451.

79. Jain A, Batista EL Jr, Serhan C, Stahl GL, van Dyke TE. Role forperiodontitis in the progression of lipid deposition in an animalmodel. Infect Immun.2003;71:6012018.

80. Nahid MA, Rivera M, Lucas A, Chan EK, Kesavalu L. Polymicrobialinfection with periodontal pathogens specifically enhancesmicroRNA miR-146a in ApoE-/- mice during experimentalperiodontal disease. Infect Immun.2011;79:1597605.

81. Nakano K, Nemoto H, Nomura R, Inaba H, YoshiokaH, Taniguchi K, Amano A, Ooshima T. Detection of oral

bacteria in cardiovascular specimens. Oral Microbiol Immunol.2009;24:6468.

82. Joshipura KJ, Wand HC, Merchant AT, Rimm EB. Periodontaldisease and biomarkers related to cardiovascular disease.J DentRes.2004;83:15155.

83. Pepys MB, Hirschfield GM. C-reactive protein: a critical update.J Clin Invest.2003;111:1805812.

84. The Cochrane Collaboration. Glossary of terms in The CochraneCollaboration. Version 4.2.5 [updated May 2005]. TheCochrane Collaboration, 2005. Available from www.cochrane-handbook.org

85. Renvert S, Lindahl C, Roos-Jansker AM, Lessem J. Short-term effects of an anti-inflammatory treatment on clinicalparameters and serum levels of C-reactive protein andproinflammatory cytokines in subjects with periodontitis. JPeriodontol.2009;80:892900.

86. Vidal F, Figueredo CM, Cordovil I, Fischer RG. Periodontaltherapy reduces plasma levels of interleukin-6, C-reactiveprotein, and fibrinogen in patients with severe periodontitis andrefractory arterial hypertension.J Periodontol.2009;80:78691.

87. Tter G, Serdar M, Kurti B, Walker SG, Atak A, ToymanU, Pinar S, Aykan T. Effects of scaling and root planing andsubantimicrobial dose doxycycline on gingival crevicular fluidlevels of matrix metalloproteinase-8, -13 and serum levels ofHsCRP in patients with chronic periodontitis. J Periodontol.2010;81:1132139.

88. Ushida Y, Koshy G, Kawashima Y, Kiji M, Umeda M, Nitta H, NagasawaT, Ishikawa I, Izumi Y. Changes in serum interleukin-6, C-reactiveprotein and thrombomodulin levels under periodontalultrasonic debridement.J Clin Periodontol.2008;35:96975.
http://www.cochrane-handbook.org/http://www.cochrane-handbook.org/http://www.cochrane-handbook.org/http://www.cochrane-handbook.org/


12/13

142 2012; 46, no.2: 131142

Kotsovilis and Slim

89. Offenbacher S, Beck JD, Moss K, Mendoza L, Paquette DW,Barrow DA, Couper DJ, Stewart DD, Falkner KL, GrahamSP, Grossi S, Gunsolley JC, Madden T, Maupome G, TrevisanM, Van Dyke TE, Genco RJ. Results from the Periodontitis and

Vascular Events (PAVE) study: a pilot multicentered, randomized,controlled trial to study effects of periodontal therapy ina secondary prevention model of cardiovascular disease. JPeriodontol. 2009;80:190201.

90. Buhlin K, Hultin M, Norderyd O, Persson L, Pockley AG,Pussinen PJ, Rabe P, Klinge B, Gustafsson A. Periodontaltreatment influences risk markers for atherosclerosis in patientswith severe periodontitis.Atherosclerosis. 2009;206:51822.

91. Amar S, Gokce N, Morgan S, Loukideli M, Van Dyke TE, VitaJA. Periodontal disease is associated with brachial arteryendothelial dysfunction and systemic inflammation.ArteriosclerThromb Vasc Biol. 2003;23:1245249.

92. Elter JR, Hinderliter AL, Offenbacher S, Beck JD, Caughey M,Brodala N, Madianos PN. The effects of periodontal therapyon vascular endothelial function: a pilot trial. Am Heart J.2006;151:47.

93. Tonetti MS, DAiuto F, Nibali L, Donald A, Storry C, ParkarM, Suvan J, Hingorani AD, Vallance P, Deanfield J. Treatmentof periodontitis and endothelial function. N Engl J Med.2007;356:91120.

94. Ramrez JH, Arce RM, Contreras A. Periodontal treatmenteffects on endothelial function and cardiovascular diseasebiomarkers in subjects with chronic periodontitis: protocol fora randomized clinical trial. Trials. 2011;12:46.

95. Kinane D, Bouchard P. Periodontal diseases and health:Consensus Report of the Sixth European Workshop onPeriodontology. J Clin Periodontol. 2008;35(Suppl. 8):33337.

96. Mealey BL, Oates TW. Diabetes mellitus and periodontaldiseases.J Periodontol. 2006;77:1289303.

97. Souther land JH, Taylor GW, Moss K, Beck JD, Offenbacher S.Commonality in chronic inflammatory diseases: periodontitis,diabetes, and coronary artery disease. Periodontol 2000.2006;40:13043.

98. Le H. Periodontal disease. The sixth complication of diabetesmellitus. Diabetes Care.1993;16:32934.

99. Scannapieco FA, Ho AW. Potential associations between chronicrespiratory disease and periodontal disease: analysis of National

Health and Nutrition Examination Survey III. J Periodontol.2001;72:5056.

100. Galton F. Correlations and their measurement, chiefly fromanthropometric data. Nature.1889;39:238.

101. Pearson K. On a form of spurious correlation which may arisewhen indices are used in the measurement of organs. Proc R SocLondon Ser A.1897;60:48998.

102. Elderton WP. Frequency-curves and correlation.London: Charlesand Edwin Layton; 1906;122.

103. Fenton TR, Tough SC, Lyon AW, Eliasziw M, Hanley DA. Causalassessment of dietary acid load and bone disease: a systematicreview & meta-analysis applying Hills epidemiologic criteria forcausality. Nutr J.2011;10:41.

104. Schnemann H, Hill S, Guyatt G, Akl EA, Ahmed F. The GRADEapproach and Bradford Hills criteria for causation.J EpidemiolCommunity Health.2011;65:39295.

105. Friedewald VE, Kornman KS, Beck JD, Genco R, Goldfine A,Libby P, Offenbacher S, Ridker PM, Van Dyke TE, Roberts WC.The American Journal of CardiologyandJournal of PeriodontologyEditors Consensus: Periodontitis and atheroscleroticcardiovascular disease. J Periodontol. 2009;80:1021032.CDHA


13/13

Copyright of Canadian Journal of Dental Hygiene is the property of Canadian Dental Hygienists Association

and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright

holder's express written permission. However, users may print, download, or email articles for individual use.

Documents

Cardiovasculer and Pd