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Introduction
Cardiovascular disease (CVD) accounts for 29% of deaths worldwide and is the second leading cause of death.1 Atherosclerosis, a major component of CVD, affects one in 4 persons and contributes to 39% of deaths annually in the United States.2 In atherosclerosis, large to medium sized muscular and large elastic arteries become occluded with fibro-lipid lesions called atheromas. End stage complications or events associated with atherosclerosis include coronary thrombosis, acute myocardial infarction (MI), and stroke. Interestingly, traditional CVD risk factors related to behaviors, diet, lifestyle, and family history do not appear to fully account for the development of atherosclerosis. Furthermore, despite continued preventive efforts addressing modifiable risk factors, mortality rates from CVD have remained virtually unchanged over the past decade in developed countries. Clinicians and investigators currently appreciate that inflammation plays a central role in the pathogenesis of atherosclerosis, including endothelial cell expression of adhesion molecules (eg, vascular cell adhesion molecule-1 or VCAM-1), development of the fatty streak, progression to a complex plaque, and rupture of plaques.3 Clinicians and investigators also understand that exposures to infections may promote some of these inflammatory changes in vessels. Implicated infections include cytomegalovirus, herpes simplex virus, Chlamydia pneumoniae, Heliobacter pylori, and periodontal disease.4 The objectives of this review are to present the latest and cumulative evidence supporting an association between cardiovascular and periodontal diseases, explain the biological plausibility for this association, and advise clinicians how to integrate these findings into practice.
Observational Evidence Relating Periodontal and Cardiovascular Diseases
Periodontal disease (oral inflammation) and CVD have several common risk factors, such as advanced age, male gender, lower socioeconomic status, stress, and smoking.5 Additionally, many patients with periodontal disease also exhibit CVD.6 These observations suggest that periodontal disease and atherosclerosis share similar or common etiologic pathways. Scannapieco and colleagues conducted a recent systematic review of the observational evidence supporting an association between periodontal disease and CVD.7 The investigators asked the focused question: "Does periodontal disease influence the initiation/progression of atherosclerosis and therefore CVD, stoke and peripheral vascular disease?" Although the investigators did not perform any meta-analysis of data from 31 identified human studies because of heterogeneity in study outcomes, the authors noted relative consistency in the findings and concluded: "Periodontal disease may be modestly associated with atherosclerosis, myocardial infarction and cardiovascular events." An accompanying consensus report approved by the American Academy of Periodontology recommends: "Patients and health care providers should be informed that periodontal intervention may prevent the onset or progression of atherosclerosis-induced diseases."
Since this review and consensus report, other meta-analyses on the cardiovascular-periodontal disease association have been conducted and published. Meurman and coworker reported a 20% increase in the risk for CVD among patients with periodontal disease (95% CI 1.08-1.32) and an even higher risk ratio for stroke, varying from 2.85 (95% CI 1.78-4.56) to 1.74 (95% CI 1.08-2.81).8 Similarly, Vettore and Khader et al reported relative risk estimates of 1.19 (95% CI 1.08-1.32) and 1.15 (95% CI 1.06-1.25), respectively.9,10 Cumulatively, these meta-analyses support a modest but statistically significant increase in the risk for CVD for patients with periodontal disease.
Several case-control and cohort studies (Table 1) conducted over the past two decades and pooled in these meta-analyses warrant detailed discussion. In 1989, Matilla et al first reported that poor oral health (including periodontal disease) was a predictor for MI among 202 Finnish subjects.11 Accordingly, the investigators found that individuals with evidence of oral infection were 30% more likely to present with MI compared to subjects without oral infections. This association was significant after adjusting for known risk factors like age, total cholesterol levels, hypertension, body mass index, and cigarette smoking. In a follow-up publication based on the same population, these investigators documented a significant and specific association between dental infections and severe coronary atheromatosis for males.12 More recently, Arbes et al evaluated cross-sectional data from the Third National Health and Nutrition Survey (NHANES III).13 They found that for cases with severe clinical attachment loss (CAL) and periodontitis, the odds ratio (OR) for self-reported MI was 3.8 (95% CI 1.5-9.7) compared to periodontally healthy controls. An early cohort study conducted by DeStefano et al reviewed data from 9,760 US adults followed for 14 years and found that individuals with pre-existing clinical signs of periodontitis were 25% more likely to develop coronary heart disease (CHD) compared to those with minimal periodontal disease after adjusting for other known risk factors.14 In this study, males younger than 50 years with periodontitis were 72% more likely to develop CHD compared to their periodontally healthy counterparts.
Beck and co-workers assessed the periodontal status of 1,147 males aged 21-80 years enrolled in the Normative Aging Study and free of CHD at baseline.15 Odds ratios adjusted for age and established cardiovascular risk factors were 1.5 (95% CI 1.0-2.1), 1.9 (95% CI 1.1-3.4), and 2.8 (95% CI 1.5-5.5) for periodontal bone loss and total CHD, fatal CHD, and stroke, respectively. When the investigators graphed the cumulative incidence of coronary heart disease or events versus baseline mean alveolar bone loss, they noted a linear relationship such that increasing severities of periodontitis were accompanied by increasing occurrences of CVD.
Beck and coworkers also collected and analyzed data on a larger population (6,017 persons ages 52-75 years) participating in the Atherosclerosis Risk in Communities (ARIC) study.16-18 Here they explored clinical CHD (MI or revascularization procedure) and subclinical atherosclerosis [carotid artery intima-media wall thickness (IMT) using B-mode ultrasound] as dependent variables in logistic regression analyses. Individuals with both high attachment loss (≥10% of sites with attachment loss ≥3 mm) and high tooth loss exhibited elevated odds of prevalent CHD as compared to individuals with low attachment loss and low tooth loss (OR=1.5, 95% CI 1.1-2.0 and OR=1.8, CI 1.4-2.4, respectively).18 A second analysis indicated a significant association between severe periodontitis and thickened carotid arteries after adjusting for covariates such as age, gender, diabetes, lipids, hypertension, and smoking.16 Accordingly, the OR for severe periodontitis (ie, 30% or more of sites with ≥3 mm clinical attachment loss) and subclinical carotid atherosclerosis was 1.31 (95% CI 1.0-1.7). In a third report, the investigators quantified serum IgG antibody levels specific for 17 periodontal organisms using a whole bacterial checkerboard immunoblotting technique.17 Analyzing mean carotid IMT (≥1 mm) as the outcome and serum antibody levels as exposures within the ARIC population, the investigators noted that the presence of antibody to Campylobacter rectus increased the risk for subclinical atherosclerosis two-fold (OR=2.3, 95% CI 1.8-2.8). In particular, individuals with both high C. rectus and Peptostreptococcus micros antibody titers had almost twice the prevalence of carotid atherosclerosis as compared to those with only a high C. rectus antibody (8.3% versus 16.3%). Stratification by smoking indicated that all microbial models significant for smokers were also significant for never smokers except for Porphyromonas gingivalis. Hence, clinical signs of periodontitis are associated with CHD and subclinical atherosclerosis in the ARIC population, and exposures to specific periodontal pathogens significantly increase the risk for atherosclerosis in smoking and nonsmoking subjects.
Several other recent population studies further support the association between periodontal disease and CVD. Joshipura and coworkers assessed self-reported periodontal disease outcomes and incident CVD in two extant databases: the Health Professional Follow-up Study (HPFS, n=41,407 males followed for 12 years) and the Nurses Health Study (NHS, n=58,974 females followed for 6 years).19 After controlling for important cardiovascular risk factors, males with a low number of reported teeth (≤ 10 at baseline) had a significantly higher risk of CHD (OR= 1.4, 95% CI 1.1-1.7) as compared to males with a high number of teeth (≥ 25). For females with the same reported extent of tooth loss, the relative risk for CHD was 1.64 (95% CI 1.3-2.1) as compared to women with at least 25 teeth. The relative risks for fatal CHD events increased to 1.8 (95% CI 1.3-2.4) for males and 1.7 (95% CI 1.1-2.5) for females with tooth loss, respectively. In a second report, the investigators evaluated the association between self-reported periodontal disease and serum elevations in CVD biomarkers cross-sectionally in a subset of HPFS participants (n=468 males).20 Serum biomarkers included C-reactive protein (CRP), fibrinogen, factor VII, tissue plasminogen activator (t-PA), low-density lipoprotein (LDL) cholesterol, von Willebrand factor, and soluble tumor necrosis factor (TNF) receptors 1 and 2. In multivariate regression models controlling for age, cigarette smoking, alcohol intake, physical activity, and aspirin intake, self-reported periodontal disease was associated with significantly higher levels of CRP (30% higher among periodontal cases compared with non-cases), t-PA (11% higher), and LDL cholesterol (11% higher). These analyses reveal significant associations between self-reported measures of periodontal disease and not only CHD, but also serum biomarkers of endothelial dysfunction and dyslipidemia.
Another US population study called Oral Infections and Vascular Disease Epidemiology Study (INVEST) was designed to further evaluate the association between atherosclerosis and periodontal outcomes. Desvarieux and coworkers first reported that for a group of 203 stroke-free subjects (ages 54 -94) at baseline, mean carotid plaque thickness (measured with B-mode ultrasound) was significantly greater among dentate subjects with severe periodontal bone loss (≥ 50% measured radiographically) as compared to those with less bone loss (< 50%).21 The group noted a clear dose-response relationship when they graphed subject tertiles of periodontal bone loss versus carotid plaque thickness. The investigators then collected subgingival plaque from 1,056 subjects and tested for the presence of 11 known periodontal bacteria using DNA techniques.22 The investigators found that cumulative periodontal bacterial burden was significantly related to carotid IMT after adjusting for CVD risk factors. Whereas mean IMT values were similar across burden tertiles for putative (orange complex) and health-associated bacteria, IMT values rose with each tertile of etiologic bacterial burden (Actinobacillus ancinomycetemcomitans, P. gingivalis, Treponema denticola, and Tannerella forsythensis). Similarly, white blood cell values but not serum CRP increased across these burden tertiles. These data from INVEST provide evidence of a direct association between oral infective organisms and subclinical atherosclerosis.
Consistent associations between periodontal and CVD outcomes have also been demonstrated for European and Asian populations. For 131 adult Swedes, mean carotid IMT values were significantly higher in subjects with clinical and/or radiographic evidence of periodontal disease as compared to periodontally healthy controls.23 Multiple logistic regression analysis identified periodontal disease as a principal independent predictor of carotid atherosclerosis with an OR of 4.6 (95% CI 1.6-13.1). Pussinen et al monitored antibody responses for A. actinomycetemcomitans and P. gingivalis among 6,950 Finnish subjects for whom CVD outcomes over 13 years were available (Mobile Clinic Health Survey).24 Compared with the subjects who were seronegative for these pathogens, seropositive subjects had an OR of 2.6 (95% CI 1.0-7.0) for a secondary stroke. In a second report on 1,023 males (Kuopio Ischemic Heart Disease Study), Pussinen and coworkers observed that cases with MI or CHD death were more often seropositive for A. actinomycetemcomitans than those controls who remained healthy (15.5% versus 10.2%).25 In the highest tertile of A. actinomycetemcomitans antibodies, the relative risk for MI or CHD death was 2.0 (95% CI 1.2-3.3) compared with the lowest tertile. For P. gingivalis antibody responses, the relative risk was of 2.1 (95% CI 1.3-3.4). Abnet and coworkers recently published findings from a cohort study of 29,584 healthy rural Chinese adults monitored for tooth loss and CVD for 15 years or less.26 Individuals with greater than the age-specific median number of teeth lost exhibited a significantly increased risk of death from MI (OR=1.3, 95% CI 1.2-1.4) and stroke (OR=1.1, 95% CI 1.0-1.2). These elevated risks were present in males and females irrespective of smoking status. Collectively, these findings indicate consistent and generalizable associations for periodontal disease and pathogenic exposures with CVD in worldwide populations.
Mechanisms Explaining Biological Plausibility
Since periodontal infections result in lowgrade bacteremias and endotoxemias in affected patients, systemic effects on vascular physiology via these exposures appear biologically plausible.27,28 Four specific pathways have been proposed to explain the plausibility of an association between CVD and periodontal infection (Figure 1). These pathways include: (1) direct bacterial effects on platelets, (2) autoimmune responses, (3) invasion and/or uptake of bacteria in endothelial cells and macrophages, and (4) endocrinelike effects of proinflammatory mediators. In support of the first pathway, two oral bacteria, P. gingivalis and Streptococcus sanguis, express virulence factors called collagen-like platelet aggregation associated proteins (PAAP) that induce platelet aggregation in vitro and in vivo.29,30 Secondly, autoimmune mechanisms may play a role since antibodies that cross-react with periodontal bacteria, and human heat shock proteins have been identified.31,32 Thirdly, Deshpande and coworkers have demonstrated that P. gingivalis can invade aortic and heart endothelial cells via fimbriae.33 Several investigative groups have independently identified specific oral pathogens in atheromatous tissues.34 In addition, macrophages incubated in vitro with P. gingivalis and LDL uptake the bacteria intracellularly and transform into foam cells.35 In the last potential pathway, systemic proinflammatory mediators are upregulated for endocrine-like effects in vascular tissues, and studies consistently demonstrate elevations in C-reactive protein and fibrinogen among periodontally diseased subjects.36-38
Effect of Periodontal Interventions on CVD Outcomes
Human evidence demonstrating beneficial effects of periodontal therapy on CVD outcomes presently is limited and indirect. D'Auito and coworkers recently demonstrated that periodontitis patients treated with scaling and root planing (SRP) exhibited significant serum reductions in the CVD biomarkers, CRP, and interleukin-6 (IL-6).39 In particular, patients who clinically responded to periodontal therapy in terms of pocket depth reductions were 4 times more likely to exhibit serum decreases in CRP relative to patients with a poor clinical periodontal response. Elter and colleagues also report decreases in these serum biomarkers plus improved endothelial function (ie, flow-mediated dilation of the brachial artery) for 22 periodontitis patients treated with "complete mouth disinfection" (ie, SRP, periodontal flap surgery, and extraction of hopeless teeth within a 2-week interval).40 Similarly, Seinost and coworkers tested endothelial function in 30 patients with severe periodontitis versus 31 periodontally healthy control subjects.41 At baseline (prior to treatment), flow-mediated dilation was significantly lower in patients with periodontitis than in control subjects. Periodontitis patients with favorable clinical responses to nonsurgical periodontal therapy (ie, SRP, topical and peroral antimicrobials plus mechanical retreatment) exhibited concomitant improvements in flow-mediated dilatation of the brachial artery and serum CRP concentrations. While the effects of periodontal therapy on CVD events in patients have yet to be determined, the available data suggest that periodontal therapies can improve surrogate CVD outcomes such as serum biomarkers and endothelial dysfunction.
Conclusions and Integrating Findings Into Clinical Practice
Inflammation plays a central role in the pathogenesis of periodontal disease and CVD. Human observational studies consistently implicate periodontal infection and the resulting oral inflammatory burden as systemic exposures that may perpetuate these inflammatory events in vessels. Although treatments aimed at decreasing periodontal therapy can reduce serum inflammatory biomarkers predictive of CVD and improve vascular responses, the clinical relevance of these surrogate changes to reduced risks for MI or stroke are not known at this time. Nevertheless, clinicians should be knowledgeable about this consistently observed association and integrate these findings into clinical practice. Physicians, dentists, and other heath care providers should appreciate that the presence of oral inflammation at least indicates an increased likelihood of CVD or events in patients who otherwise exhibit the traditional risk factors. While medicine and dentistry currently lack the definitive evidence establishing causality, clinicians should identify patients exhibiting signs of oral inflammation, appropriately educate them about the current level of evidence on the risk association, and implement preventive strategies that can improve oral health and systemic well being
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About the Author
David W. Paquette, DMD, MPH, DMSc
Department of Periodontology, Center for Oral and Systemic Diseases
University of North Carolina School of Dentistry
