Dental Infections and CardiovascularDiseases: A ReviewKimmo J. Mattila,* Pirkko J. Pussinen,† and Susanna Paju†

Accumulating evidence suggests that chronic infections, suchas periodontitis, are associated with increased risk for cardio-vascular diseases (CVD). The mechanisms behind the associa-tion are not known. Like herpes viruses and Chlamydiapneumoniae, periodontal pathogens cause atherosclerosis inexperimental animals and have been found in human athero-sclerotic lesions. Higher concentrations of total and low densitylipoprotein (LDL) cholesterol and triglycerides and lower con-centrations of high density lipoprotein (HDL) cholesterol havebeen observed in individuals with periodontitis before periodon-tal treatment. Periodontitis also induces a peripheral inflamma-tory and immune response, reflected in elevated concentrationsof C-reactive protein (CRP) and IgA-class antibodies to peri-odontal pathogens. The prevalence of CVD seems to be high-est in those individuals in whom periodontitis coexists withelevated CRP levels. This may indicate that periodontitis isa CVD risk factor in individuals who react to the infectionwith a systemic inflammatory and immune response. Thismay be due to genetic reasons and may also apply to otherchronic low-grade infections. J Periodontol 2005;76:2085-2088.

KEY WORDS

Atherosclerosis; cardiovascular diseases; coronary heartdisease; Periodontitis.

Infections were proposed to be riskfactors for cardiovascular diseases(CVD) by Osler about 100 years

ago.1 The hypothesis remained largelyforgotten until Fabricant et al. showed inthe 1970s that the Marek’s disease virus(a herpes virus) can cause atheroscle-rosis in experimental animals.2 Impor-tantly, subsequent studies showed thatinfection and hypercholesterolemia hada synergistic effect. After that, a largenumber of studies suggested that infec-tions are linked with CVD. The list ofinfections incriminated includes bothacute and chronic infections of bothviral and bacterial origin (e.g., influenza,herpes viruses, upper respiratory infec-tions, Helicobacter pylori, Chlamydiapneumoniae, with dental infections [car-ies and periodontitis]). However, due toseveral confounding factors and meth-odological difficulties, the true nature ofthe association between infections andCVD has proved difficult to elucidate.There are also several studies in whichno association has been found.3-7 Thisarticle reviews data linking dental infec-tions with CVD, with an emphasis on themost recent findings.

REVIEW OF RECENT STUDIES

Cross-Sectional and ObservationalStudiesThe first observations linking dental in-fections and CVD came from case-control studies.8,9 These studies werecriticized since it can be argued thatcase-control design is not ideal in situa-tions where several confounding factorsexist between the risk factor candidate

* Helsinki University Central Hospital, Division of Infectious Diseases, Helsinki, Finland.† Institute of Dentistry, University of Helsinki, and Department of Oral and Maxillofacial

Diseases, Helsinki University Central Hospital.

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and the disease studied. Subsequently, several stud-ies also with a follow-up design of various cohortshave been published. These data have recently beenreviewed comprehensively by Scannapieco et al.,10

who concluded that there is an independent, modestassociation between periodontitis and CVD.

It is important to note that the differences in thepopulations studied and the lack of standard defini-tions and measures for periodontitis make the datahard to interpret. The association between periodon-titis and CVD is complex and dependent on many fac-tors, including the age of the population studied.11

The published studies may have included both popu-lations, with a strong association between periodonti-tis and CVD and populations in which this associationis weak or absent.

Animal StudiesThe effect of periodontitis on the development of ath-erosclerosis has also been studied in animal models.Repeated intravenous administration of Porphyromo-nas gingivalis enhanced progression of atherosclero-sis in the proximal aortas of apoE-deficient mice.12

Oral and anal application of P. gingivalis inducedearly atherosclerotic lesions in apoE-null mice.13,14

In the aortas of New Zealand white rabbits, P. gingiva-lis generated lipid accumulation, which had a correla-tion with the severity of periodontitis.15 In this context,it is of note that both P. gingivalis DNA and viablepathogens have been found in human atheroscleroticlesions.16,17 The observations bear a resemblancewith other microbes that are associated with CVD.Herpes viruses and C. pneumoniae cause atheroscle-rotic changes in mice, and the effects are enhanced byhypercholesterolemia. Various herpes viruses and C.pneumoniae have also been found in human athero-sclerotic lesions.18

The results of animal studies must be interpretedwith caution, since findings in experimental animalscannot be directly transferred to humans. Further-more, existence of various microbes in human athero-sclerotic lesions does not necessarily prove that theyhave caused the lesions.

However, endothelial dysfunction, an early step inthe pathogenesis of atherosclerosis, has been shownto occur in individuals with periodontitis19 as well as inhealthy individuals after Salmonella typhi vaccina-tion.20

Effects of Periodontitis on Lipids, Inflammation,and Immune ResponseRecently, increasing attention has been paid to the ef-fect of periodontitis on lipoproteins and inflammation,two major contributors to the pathogenesis of CVD.The key role of lipid levels as a CVD risk factor hasbeen known for years. It is also well established that

acute infections influence lipoprotein levels – as a partof the acute-phase reaction – in a way that may favoratherogenesis.21 The effects of chronic, low-grade in-fections such as periodontitis are less well known. Incross-sectional studies, periodontitis has been associ-ated with elevated levels of total and LDL cholesteroland/or triglycerides and decreased levels of HDLcholesterol.22-27

Recent data suggest that periodontitis may havemore subtle but broad effects on the metabolismand properties of lipoproteins that may be reversedby periodontal treatment.

In 30 adult patients with chronic periodontitis, thenumber of periodontal sites with bleeding on probingcorrelated positively with serum lipopolysaccharide(LPS) concentration.28 Furthermore, the number ofteeth with deepened periodontal pockets correlatedwith the ability of the LDL isolated from these individu-als to induce cytokine production anduptake of choles-teryl ester by mouse macrophages.28 These twophenomena are considered atherogenic, since theyleadtomacrophage-derivedfoamcell formation,ahall-mark of early atherosclerosis. After periodontal treat-ment, significant increases were observed in serumHDL cholesterol concentration, HDL2/HDL3 ratio, andHDL phospholipid content and sphingomyelin/phos-phatidylcholine ratio.29 Inaddition, individualswithhighbaseline concentrations of serum LPS had significantlyhigher HDL/LDL ratio, lower anti-b2-glycoprotein Iantibodies and LPS concentrations, and larger LDLparticle size after periodontal treatment. In individualswith low baseline LPS concentrations, changes inthese parameters were only minor.28 In those individ-uals whose baseline CRP concentrations decreasedsignificantly after periodontal treatment and who har-bored subgingival Actinobacillus actinomycetemco-mitans, the HDL-mediated cholesterol efflux frommouse macrophages was significantly higher afterthe treatment.29 Cholesterol efflux from macrophagesis the first step in reverse cholesterol transport, theanti-atherogenic pathway where excess cholesterol isremoved from peripheral cells to the liver for excretion.

Previously, it was not possible to identify and ex-plore the peripheral effects of periodontitis. Now thatmore sensitive techniques have become available,‘‘the degree of inflammation’’ in periodontal diseasehas shown to be sufficient to cause a systemic inflam-matory response, as evidenced by increases in CRP.30

This inflammatory response is reflected in severalother inflammatory markers in a mouse model: seruminterleukin-6 (IL-6), vascular cell adhesion molecule-1(VCAM-1), and tissue factor antigen.13 Importantly,treatment of periodontitis has been shown to decreaseCRP levels.31,32 CRP is not elevated in all patients withperiodontitis or other low-grade infections associatedwith CVD. Interestingly, CVD risk seems to be highest

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among those who show both evidence of somechronic, low-grade infection and elevated CRP.33-36

As shown also for C. pneumoniae,37 persistently el-evated serum IgA-class antibodies to major periodon-tal pathogens appear to predict CVD incidence. Ina population of 6,950 subjects, IgA-seropositivityfor P. gingivalis predisposed to stroke in subjects witha history of CVD (odds ratio [OR] 2.6, 95% confidenceinterval [CI] 1.0 to 7.0), whereas seropositivity for A.actinomycetemcomitans was associated with strokeincidence in subjects free from CVD at baseline (OR1.6, 95% CI 1.0 to 2.6).38 In another large prospectivestudy comprising 1,023 men, high antibody levelswere associated with subclinical, prevalent, and futureincidence of coronary heart disease (OR 2.0 to 2.1).39

In a smaller prospective study, high IgA-class anti-body levels to P. gingivalis increased the risk for myo-cardial infarction by 300% (OR 4.0, 95% CI 1.2 to13.1) in a North Karelian Finnish population with anexceptionally high prevalence of CHD.40 Althoughthe significance of serum IgA-class antibodies is notfully understood, they are believed to indicate persis-tent periodontitis with active tissue destruction.41

CONCLUSIONS

Periodontitis may not be confined only to a localizeddisease process. It has peripheral effects that includeproatherogenic changes in lipoproteins and systemicinflammatory and immune responses. Interplay be-tween altered lipoproteins and inflammation is recog-nized as a key factor in the pathogenesis ofatherosclerosis.42 Periodontitis could bear a signifi-cant CVD risk, since it is a long-term disease processwith a relatively high prevalence in Western popula-tions and may not always respond to treatment. Ob-servations that the risk is highest in individuals withperiodontitis and elevated CRP concentrations andserum antibody levels to periodontal pathogensmay suggest that periodontitis increases CVD riskmostly in individuals who react to these infectionsby a systemic inflammatory and immune response.This may be due to genetic reasons and may also ap-ply to other chronic, low-grade infections, such asthose caused by herpes viruses and C. pneumoniae.

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Correspondence: Dr. Kimmo J. Mattila, Haartmaninkatu 4,00290 Helsinki, Finland. E-mail: kimmo.mattila@hus.fi.

Accepted for publication January 26, 2005.

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