- Email: [email protected]
A perspective on the potential cardioprotective benefits of periodontal therapy
Editorial
A perspective on the potential cardioprotective benefits of periodontal therapy Steven Offenbacher, DDS, PhD, MMSc, and James D. Beck, PhD Chapel Hill, NC
See related article on page 1050.
In recent years, the concepts of the pathogenesis of atherosclerosis and cardiovascular events have broadened from a lipid-centric view of etiology to the appreciation of the importance of the inflammatory processes. Although obesity, oxidized lipids, and other factors are known to contribute to cardiovascular inflammation, the role of infection is believed to serve as a critical inflammatory stimulus that contributes to both atherogenesis and acute events via plaque destabilization. This inflammatory process can involve the vasculature directly by interaction of the organisms or bacterial byproducts with the vessel wall or indirectly via modulation of hemostasis or hepatic activation of the acute phase response that leads to increased circulating levels of acute-phase reactants such as C-reactive protein (CRP). Epidemiological studies have suggested a significant moderate association between periodontal infection and cardiovascular risk adjusting for traditional risk factors. The potential role of periodontal disease as a possible chronic source of infection and inflammation is supported by findings indicating an association of periodontal disease with elevated serum CRP and interleukin 6. Recently, periodontal therapy studies have shown a lowering of CRP and interleukin 6, and in this issue, a new report of an improvement of endothelial function, as measured by flow-mediated dilation. These studies raise the possibility that periodontal disease may represent a modifiable risk factor that merits further study. Epidemiological studies have provided the first line of evidence to suggest that periodontal infections may increase the risk for heart disease. Several studies have shown an association between more severe periodontal disease and increased risk for acute cardiovascular events such as myocardial infarction (MI), stroke, and revascularization procedures, after adjusting for
From the Departments of Periodontology and Dental Ecology, Center for Oral and Systemic Diseases, School of Dentistry, University of North Carolina, Chapel Hill, NC. Submitted January 13, 2005; accepted January 17, 2005. Reprint requests: Steven Offenbacher DDS, PhD, MMSc, Center for Oral and Systemic Diseases, CB #7455, DRC Room 222, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455. E-mail: steve [email protected] Am Heart J 2005;149:950- 4. 0002-8703/$ - see front matter n 2005, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2005.01.046
traditional cardiovascular risk factors such as age, sex, smoking, obesity, and blood lipids.1 Periodontal disease has also been associated with increased carotid intima- medial wall thickness, as a measure of subclinical atherosclerosis.2,3 Overall, there have been approximately 42 cross-sectional, case-control, or longitudinal studies published that have examined the potential association between periodontal disease and cardiovascular disease, and 80% have shown significant positive associations. Among the 16 longitudinal studies, 10 have shown that periodontal disease is significantly associated with an increased risk for cardiovascular events even after adjustment for a variety of potential confounders. However, as reviewed previously,4 the majority of reports of association represent secondary analyses of existing data sets (primarily 2 large studies) that were not initially intended to examine the relationships between oral infection and cardiovascular disease. It has been suggested1 that this limitation, when coupled with other methodological problems such as indirect, inadequate, or incomplete measurements of exposure and outcome, has lead to inconsistencies in the reported findings, leading some investigators to question both the magnitude and the significance of these reported associations. Thus, the field of study that is examining the linkages between periodontitis and cardiovascular disease is relatively immature. Nonetheless, in a recent review by Janket and Baird,5 a metaanalyses was performed, pooling available study data. This report concluded that there is a significant association between clinical periodontal disease and cardiovascular disease with an adjusted odds ratio (OR) of 2.85 for stroke, 1.19 for cardiovascular diseases, and 1.44 for cardiovascular events in subjects aged V65 years.5 Thus, the current opinion, although based on data of uneven quality, seems to favor a mild to moderate association between periodontal disease and increased cardiovascular risk. However, the associations are stronger, if one limits the consideration of all available studies to those few that include (1) direct clinical measures of periodontal disease and cardiovascular status, (2) standardized and calibrated examiners, and (3) adequate adjustment of relevant covariates and confounders. For example, Figure 1 is adapted from data reported by Beck et al2 and shows the distribution of mean carotid artery intima-media thickness (IMT) measures (in millimeters) among 6149
American Heart Journal Volume 149, Number 6
Offenbacher and Beck 951
Figure 1
No Periodontal Disease Periodontal Disease
30
Percent of Persons
25 20 15
IMT = 1.0 mm, 90th Percentile 10 5 0 .4
-5
<0
9
9
9 .6
.5
.4
-0
4 0.
-0
5 0.
-0
6 0.
9
.8
.7
-0
7 0.
-0
8 0.
9
9 .0
9
.9
9-
0.
-1
0 1.
9 .1
-1
1 1.
9 .2
-1
2 1.
9 .3
-1
3 1.
9 .4
-1
4 1.
IMT Distribution of IMT by periodontitis status among persons with no history of coronary heart disease (N = 6149). Adapted from Beck et al.2
community-dwelling subjects enrolled in the ARIC study based upon periodontal disease status. Subjects with a clinical diagnosis of coronary heart disease were excluded from these analyses, so the IMT thickness reflects subclinical atherosclerosis, and the 1-mm threshold indicates those with thick IMT at the 90th percentile. It can be seen that among subjects with severe periodontal disease (defined as at least 60% of periodontal sites with z3-mm attachment loss), there is a shift to the right in the frequency distribution of IMT thickness reflecting an overall increase in IMT among subjects with periodontal disease. There is a marked increase in the prevalence of thicker IMT levels as one examines the tail of the distribution of IMT values N0.9 mm. The odds of IMT z1.0 mm were higher in severe periodontitis (OR 2.09, 95% CI 1.73-2.53) in multivariable logistic regression models adjusting for age, sex, diabetes, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, hypertension, smoking, waist/hip ratio, education, and race/center.2 These data suggest that periodontal disease may independently contribute to the pathogenesis of atheroma formation. In addition, it can be argued that periodontal disease is simply a marker for some other either unknown or uncontrolled underlying risk factor or exposure. Clearly, additional studies are needed to assess causality, and interventional trials are needed to determine whether treating periodontal disease will modify the incidence of cardiovascular disease. It is in this context that the investigation presented by Seinhost et al entitled bPeriodontal treatment improves endothelial dysfunction in patients with severe perio-
dontitisQ presents novel findings that demonstrate the potential systemic benefits of periodontal therapy. Although previous studies have shown that periodontal treatment reduces other cardiovascular risk factors, such as C-reactive protein (CRP) and interleukin (IL) 6, this is the first report that demonstrates a functional improvement in cardiovascular health after periodontal treatments. The Seinhost et al report demonstrates that periodontal therapy, which reduces the oral infection burden, results in an improvement in endothelial function as assessed by flow-mediated dilation. To cardiology investigators and clinicians, this finding may seem at first to be a rather spurious or obtuse observation. The purpose of this editorial is to place these findings into a plausible biologic framework by summarizing briefly what is known regarding the underlying pathobiology of the oral infection–cardiovascular disease connection and why periodontal therapy merits further study as a potentially new cardioprotective therapy.
Periodontal disease is a common biofilm infection that disseminates systemically Mild forms of periodontal disease affect three fourths of the population, whereas more severe forms affect about 1 in 5 adults in the United States. Although the magnitude of the systemic microbial and inflammatory stress caused by chronic periodontal diseases may be small compared to severe acute infections such as pneumonia, periodontitis is both widespread and often persists for decades. Thus, the total burden of this infection may be significant. Specifically, it may account
952 Offenbacher and Beck
for a portion of the proposed risk for cardiovascular disease and other systemic conditions that share an underlying inflammatory response as a common component of pathogenesis. Furthermore, the chronic and cyclic nature of the periodontal condition provides opportunity for repeated hematogenous dissemination of periodontal pathogens and direct exposure of the vasculature and the liver to oral microbes and oral endotoxins (see Ref. [6] for review). The periodontal organisms, which are largely gram-negative anaerobes, live in a biofilm underneath the gum line around the teeth and have no other ecological habitat but the periodontal pocket area. These organisms have coevolved with us and have adapted to survive within this hostile oral environment that is constantly besieged by host defenses including serum antibody and complement, phagocytic leukocytes, and salivary proteins. These oral organisms not only persist in the periodontal pocket biofilm, but also in the presence of inflammation; they flourish, enabling their capacity to invade into host tissues and gain direct access into the circulation.6 As a consequence of this tissue-invasive property, not only are repeated bacteremias and endotoxemias characteristics of periodontal infections, there have also been reports of periodontal organisms colocalizing within atheromatous plaques, as detected by polymerase chain reaction methods.7 These studies suggest that periodontal pathogens may be present in atherosclerotic plaques where, like other infectious organisms such as Chlamydia pneumoniae, they may play a role in development and progression of atherosclerosis. Thus, the repeated exposure of the vasculature to these pathogens provides a clear opportunity for endothelial inflammatory activation and functional impairment.
Periodontitis increases systemic inflammation as measured by serum CRP and IL-6 Periodontitis appears to be one important infectious and inflammatory stressor that can increase the hepatic synthesis of CRP, which is a recognized predictor of acute MI and stroke. The most comprehensive study to date demonstrating an association of periodontitis with moderately elevated serum CRP concentration was reported by Slade and Ghezzi.8 In this study, a random sample of the US population (14 766 subjects) was interviewed in their homes and received periodontal exams at mobile examination centers. CRP was quantified by high-sensitivity (hs) enzyme-linked immunosorbent assay from peripheral blood samples and analyzed as a continuous variable and as the prevalence of elevated CRP (z10 mg/L). Dentate people with extensive periodontal disease (N10% of sites with periodontal pockets N4 mm) were associated with an increase of approximately one third in mean CRP and a
American Heart Journal June 2005
doubling in prevalence of elevated CRP compared with periodontally healthy people. Raised CRP levels among people with extensive periodontal disease persisted in multivariate analyses ( P b .01), adjusting for established risk factors for elevated CRP. Slade and Ghezzi9 also evaluated the association between periodontal disease and CRP levels in adults using the ARIC study. Periodontal disease was quantified as the percentage of periodontal sites with pocket depth of z4 mm. Serum hs-CRP concentration was quantified in milligrams per liter using a high-sensitivity enzyme-linked immunosorbent assay. In a multivariable linear regression model that controlled for age, sex, diabetes mellitus, cigarette use, and nonsteroidal anti-inflammatory drug use, the association of extensive periodontal pockets with hs-CRP concentration was modified by body mass index (BMI). For people with a BMI of 20, the model predicted a 2-fold difference in mean CRP concentration between periodontal pocket groups (7.5 vs 3.6 mg/L), but the difference decreased with increasing BMI and was negligible when BMI equaled 35. Thus, it appears that extensive periodontal disease and BMI are jointly associated with increased CRP levels in otherwise healthy middle-aged adults, suggesting the need for joint medical and periodontal diagnoses when evaluating sources of acute-phase response in some patients. In case-control studies, Ebersole and Machen,10 Loos and Hutter,11 Noack and Genco,12 and Amar et al13 showed that CRP levels were elevated in patients with periodontal disease as compared with periodontally healthy individuals. Loos and Hutter11 also showed that this elevation was not associated with seropositivity to C pneumoniae, cytomegalovirus, or Helicobacter pylori in subjects with periodontal disease. Amar et al13 showed an association of periodontal disease with both increased CRP and impaired endothelial function as measured by brachial flow-mediated dilation. Studies by Deliargyris et al14 demonstrated that patients with acute myocardial infection who had periodontal disease had significantly higher CRP levels than patients with acute MI who did not have periodontal disease (50.7 vs 30.7 mg/L, P b .001). In a multivariate linear regression analysis that included smoking, diabetes mellitus, and infarct size, a positive relationship was shown between the extent of periodontal disease and serum CRP levels. Periodontal disease emerged as a strong and independent predictor of elevated CRP levels after MI (r 2 = 0.33, P b .004). Some studies15,16 have demonstrated that mild and moderate periodontitis are both associated with incremental increases in serum IL-6, as well as CRP, but one study17 failed to see an association with increased IL-6 when examined in an elderly population. Interestingly, D’Aiuto et al16 have recently shown that serum IL-6 and CRP are higher among severe periodontitis patients carrying rare alleles for functional inflammatory
American Heart Journal Volume 149, Number 6
gene polymorphisms. Specifically, these investigators report increased serum IL-6 among periodontitis subjects with allele 2 for functional polymorphisms in IL-1A, tumor necrosis factor a, and IL-6 genes. Serum CRP levels were associated with allele 2 in the IL-1A and IL-6 genes. This finding is consistent with the concept that periodontal infectious exposure may be potentially more deleterious to cardiovascular health in the presence of a host genotype that favors a robust activation of the innate immune response.
Periodontal therapy decreases systemic inflammation and improves endothelial function Ebersole and Machen10 were the first to report an association between periodontal disease and increased levels of CRP, and their pilot data using periodontal treatment (scaling and root planing) and nonsteroidal anti-inflammatory drug treatment (flurbiprofen) also suggested that certain treatments can potentially lower serum CRP levels. A recent controlled clinical intervention study reported by D’Aiuto indicates that more traditional periodontal therapy (scaling and root planing alone) can significantly reduce not only CRP, but also serum IL-6 levels.16 These investigators report that among the 94 periodontitis subjects treated, significant reductions in serum IL-6 (median decrease 0.2 ng/L, 95% CI 0.1-0.4 ng/L, P b .001) and CRP (median decrease 0.5 mg/L, 95% CI 0.4-0.7, P b .0001) were observed 6 months after treatment. Although the median reductions in CRP were modest, patients who had a better response to periodontal therapy were also more likely to have decreases in their American Heart Association CRP risk category (OR 4.8, 95% CI 1.4-15.8) adjusting for age, sex, ethnicity, and smoking.18 Collectively, these data suggest that periodontal disease may be associated with mild increases in CRP (a point estimate increase of 2.7 mg/L, based upon data by Slade and Ghezzi9) and perhaps higher levels of serum IL-6. Increased serum IL-6 is mechanistically relevant to these findings, as it is not only a potent inflammatory inducer of hepatic CRP synthesis, but it is also an activator of endothelial inflammation. Thus, the IL-6 cytokinemia associated with periodontal disease may, in part, contribute to the observed association of impaired endothelial function, as measured by the hypoxia-stimulated nitric oxide– mediated hyperemia response. However, the findings by Slade and Ghezzi9 caution us, in that in an obese individual, periodontal therapy may not result in any decrease in CRP, perhaps a reflection of the linkages between obesity and increased serum IL-6. The report of Seinhost et al is significant because it provides the first evidence that treating periodontal disease results in a functional improvement in cardiovascular status.
Offenbacher and Beck 953
All of these studies are consistent with the concept that periodontal disease may be a previously underappreciated source of infectious and inflammatory vascular stress that has the potential to result in pathology of significant magnitude and prevalence. However, it is critical to emphasize that large, randomized, multicentered trials have not yet been conducted to definitively demonstrate the potential benefits of periodontal therapy to reduce the levels of CRP, or more importantly whether periodontal treatments reduce overall cardiovascular risk. What is encouraging from a health care perspective is that periodontal disease represents a potentially modifiable risk factor that is both preventable and treatable with predictable treatments that pose negligible risk. Considering that at the very least, periodontal therapy would improve oral health, we suggest that periodontal therapy as an integral component of preventive cardiology treatment is worthy of further study in both longitudinal clinical studies designed to test causality, as well as multicentered trials designed to evaluate the potential cardioprotective effects of periodontal treatment.
References 1. Genco R, Offenbacher S, et al. Periodontal disease and cardiovascular disease: epidemiology and possible mechanisms. J Am Dent Assoc 2002;133(Suppl):14S - 22S. 2. Beck JD, Elter JR, Heiss G, et al. Relationship of periodontal disease to carotid artery intima-media wall thickness the atherosclerosis risk in communities (ARIC) study. Arterioscler Thromb Vasc Biol 2001; 21:1816 - 22. 3. Desvarieux M, Demmer R, et al. Relationship between periodontal disease, tooth loss, and carotid artery plaque: the oral infections and vascular disease epidemiology study (INVEST). Stroke 2003;34: 2120 - 5. 4. Beck JD, Offenbacher S. The association between periodontal diseases and cardiovascular diseases: a state-of-the-science review. Ann Periodontol 2001;6:9 - 15. 5. Janket SJ, Baird AE, et al. Meta-analysis of periodontal disease and risk of coronary heart disease and stroke. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2003;95:559 - 69. 6. Offenbacher S, Elter JR, Lin D, et al. Evidence for periodontitis as a tertiary vascular infection. J Int Acad Periodontol 2005;7:39 - 48. 7. Haraszthy VI, Zambon JJ, Trevisan M, et al. Identification of periodontal pathogens in atheromatous plaques. J Periodontol 2000;71:1554 - 60. 8. Slade GD, Ghezzi EM, et al. Acute-phase inflammatory response to periodontal disease in the US population. J Dent Res 2000; 79:49 - 57. 9. Slade GD, Ghezzi EM, et al. Relationship between periodontal disease and C-reactive protein among adults in the atherosclerosis risk in communities study. Arch Intern Med 2003;163: 172 - 9. 10. Ebersole J, Machen R, et al. Systemic acute-phase reactants, C-reactive protein and haptoglobin in adult periodontitis. Clin Exp Immunol 1997;107:347 - 52.
954 Offenbacher and Beck
11. Loos B, Hutter J, et al. Levels of C-reactive protein in periodontitis patients and healthy controls. J Dent Res 1998;77:666. 12. Noack B, Genco RJ, et al. Periodontal infections contribute to elevated systemic C-reactive protein level. J Periodontol 2001;72:1221 - 7. 13. Amar S, Gokce N, Morgan S, et al. Periodontal disease is associated with brachial artery endothelial dysfunction and systemic inflammation. Arterioscler Thromb Vasc Biol 2003;23:1245 - 9. 14. Deliargyris EN, Madianos PN, Kadoma W, et al. Periodontal disease in patients with acute myocardial infarction: prevalence and contribution to elevated C-reactive protein levels. Am Heart J 2004;147:1005 - 9.
American Heart Journal June 2005
15. Loos BG, Craandijk J, et al. Elevation of systemic markers related to cardiovascular diseases in the peripheral blood of periodontitis patients. J Periodontol 2000;71:1528 - 34. 16. D’Aiuto F, Parkar M, Andreou G, et al. Periodontitis and systemic inflammation: control of the local infection is associated with a reduction in serum inflammatory markers. J Dent Res 2004;83: 156 - 60. 17. Murata T, Miyazaki H, et al. Periodontitis and serum interleukin-6 levels in the elderly. Jpn J Infect Dis 2001;54:69 - 71. 18. D’Aiuto F, Ready D, Tonetti MS. Periodontal disease and C-reactive protein–associated cardiovascular risk. J Periodontal Res 2004;39: 236 - 41.
A perspective on the potential cardioprotective benefits of periodontal therapy Steven Offenbacher, DDS, PhD, MMSc, and James D. Beck, PhD Chapel Hill, NC
See related article on page 1050.
In recent years, the concepts of the pathogenesis of atherosclerosis and cardiovascular events have broadened from a lipid-centric view of etiology to the appreciation of the importance of the inflammatory processes. Although obesity, oxidized lipids, and other factors are known to contribute to cardiovascular inflammation, the role of infection is believed to serve as a critical inflammatory stimulus that contributes to both atherogenesis and acute events via plaque destabilization. This inflammatory process can involve the vasculature directly by interaction of the organisms or bacterial byproducts with the vessel wall or indirectly via modulation of hemostasis or hepatic activation of the acute phase response that leads to increased circulating levels of acute-phase reactants such as C-reactive protein (CRP). Epidemiological studies have suggested a significant moderate association between periodontal infection and cardiovascular risk adjusting for traditional risk factors. The potential role of periodontal disease as a possible chronic source of infection and inflammation is supported by findings indicating an association of periodontal disease with elevated serum CRP and interleukin 6. Recently, periodontal therapy studies have shown a lowering of CRP and interleukin 6, and in this issue, a new report of an improvement of endothelial function, as measured by flow-mediated dilation. These studies raise the possibility that periodontal disease may represent a modifiable risk factor that merits further study. Epidemiological studies have provided the first line of evidence to suggest that periodontal infections may increase the risk for heart disease. Several studies have shown an association between more severe periodontal disease and increased risk for acute cardiovascular events such as myocardial infarction (MI), stroke, and revascularization procedures, after adjusting for
From the Departments of Periodontology and Dental Ecology, Center for Oral and Systemic Diseases, School of Dentistry, University of North Carolina, Chapel Hill, NC. Submitted January 13, 2005; accepted January 17, 2005. Reprint requests: Steven Offenbacher DDS, PhD, MMSc, Center for Oral and Systemic Diseases, CB #7455, DRC Room 222, School of Dentistry, University of North Carolina, Chapel Hill, NC 27599-7455. E-mail: steve [email protected] Am Heart J 2005;149:950- 4. 0002-8703/$ - see front matter n 2005, Elsevier Inc. All rights reserved. doi:10.1016/j.ahj.2005.01.046
traditional cardiovascular risk factors such as age, sex, smoking, obesity, and blood lipids.1 Periodontal disease has also been associated with increased carotid intima- medial wall thickness, as a measure of subclinical atherosclerosis.2,3 Overall, there have been approximately 42 cross-sectional, case-control, or longitudinal studies published that have examined the potential association between periodontal disease and cardiovascular disease, and 80% have shown significant positive associations. Among the 16 longitudinal studies, 10 have shown that periodontal disease is significantly associated with an increased risk for cardiovascular events even after adjustment for a variety of potential confounders. However, as reviewed previously,4 the majority of reports of association represent secondary analyses of existing data sets (primarily 2 large studies) that were not initially intended to examine the relationships between oral infection and cardiovascular disease. It has been suggested1 that this limitation, when coupled with other methodological problems such as indirect, inadequate, or incomplete measurements of exposure and outcome, has lead to inconsistencies in the reported findings, leading some investigators to question both the magnitude and the significance of these reported associations. Thus, the field of study that is examining the linkages between periodontitis and cardiovascular disease is relatively immature. Nonetheless, in a recent review by Janket and Baird,5 a metaanalyses was performed, pooling available study data. This report concluded that there is a significant association between clinical periodontal disease and cardiovascular disease with an adjusted odds ratio (OR) of 2.85 for stroke, 1.19 for cardiovascular diseases, and 1.44 for cardiovascular events in subjects aged V65 years.5 Thus, the current opinion, although based on data of uneven quality, seems to favor a mild to moderate association between periodontal disease and increased cardiovascular risk. However, the associations are stronger, if one limits the consideration of all available studies to those few that include (1) direct clinical measures of periodontal disease and cardiovascular status, (2) standardized and calibrated examiners, and (3) adequate adjustment of relevant covariates and confounders. For example, Figure 1 is adapted from data reported by Beck et al2 and shows the distribution of mean carotid artery intima-media thickness (IMT) measures (in millimeters) among 6149
American Heart Journal Volume 149, Number 6
Offenbacher and Beck 951
Figure 1
No Periodontal Disease Periodontal Disease
30
Percent of Persons
25 20 15
IMT = 1.0 mm, 90th Percentile 10 5 0 .4
-5
<0
9
9
9 .6
.5
.4
-0
4 0.
-0
5 0.
-0
6 0.
9
.8
.7
-0
7 0.
-0
8 0.
9
9 .0
9
.9
9-
0.
-1
0 1.
9 .1
-1
1 1.
9 .2
-1
2 1.
9 .3
-1
3 1.
9 .4
-1
4 1.
IMT Distribution of IMT by periodontitis status among persons with no history of coronary heart disease (N = 6149). Adapted from Beck et al.2
community-dwelling subjects enrolled in the ARIC study based upon periodontal disease status. Subjects with a clinical diagnosis of coronary heart disease were excluded from these analyses, so the IMT thickness reflects subclinical atherosclerosis, and the 1-mm threshold indicates those with thick IMT at the 90th percentile. It can be seen that among subjects with severe periodontal disease (defined as at least 60% of periodontal sites with z3-mm attachment loss), there is a shift to the right in the frequency distribution of IMT thickness reflecting an overall increase in IMT among subjects with periodontal disease. There is a marked increase in the prevalence of thicker IMT levels as one examines the tail of the distribution of IMT values N0.9 mm. The odds of IMT z1.0 mm were higher in severe periodontitis (OR 2.09, 95% CI 1.73-2.53) in multivariable logistic regression models adjusting for age, sex, diabetes, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglycerides, hypertension, smoking, waist/hip ratio, education, and race/center.2 These data suggest that periodontal disease may independently contribute to the pathogenesis of atheroma formation. In addition, it can be argued that periodontal disease is simply a marker for some other either unknown or uncontrolled underlying risk factor or exposure. Clearly, additional studies are needed to assess causality, and interventional trials are needed to determine whether treating periodontal disease will modify the incidence of cardiovascular disease. It is in this context that the investigation presented by Seinhost et al entitled bPeriodontal treatment improves endothelial dysfunction in patients with severe perio-
dontitisQ presents novel findings that demonstrate the potential systemic benefits of periodontal therapy. Although previous studies have shown that periodontal treatment reduces other cardiovascular risk factors, such as C-reactive protein (CRP) and interleukin (IL) 6, this is the first report that demonstrates a functional improvement in cardiovascular health after periodontal treatments. The Seinhost et al report demonstrates that periodontal therapy, which reduces the oral infection burden, results in an improvement in endothelial function as assessed by flow-mediated dilation. To cardiology investigators and clinicians, this finding may seem at first to be a rather spurious or obtuse observation. The purpose of this editorial is to place these findings into a plausible biologic framework by summarizing briefly what is known regarding the underlying pathobiology of the oral infection–cardiovascular disease connection and why periodontal therapy merits further study as a potentially new cardioprotective therapy.
Periodontal disease is a common biofilm infection that disseminates systemically Mild forms of periodontal disease affect three fourths of the population, whereas more severe forms affect about 1 in 5 adults in the United States. Although the magnitude of the systemic microbial and inflammatory stress caused by chronic periodontal diseases may be small compared to severe acute infections such as pneumonia, periodontitis is both widespread and often persists for decades. Thus, the total burden of this infection may be significant. Specifically, it may account
952 Offenbacher and Beck
for a portion of the proposed risk for cardiovascular disease and other systemic conditions that share an underlying inflammatory response as a common component of pathogenesis. Furthermore, the chronic and cyclic nature of the periodontal condition provides opportunity for repeated hematogenous dissemination of periodontal pathogens and direct exposure of the vasculature and the liver to oral microbes and oral endotoxins (see Ref. [6] for review). The periodontal organisms, which are largely gram-negative anaerobes, live in a biofilm underneath the gum line around the teeth and have no other ecological habitat but the periodontal pocket area. These organisms have coevolved with us and have adapted to survive within this hostile oral environment that is constantly besieged by host defenses including serum antibody and complement, phagocytic leukocytes, and salivary proteins. These oral organisms not only persist in the periodontal pocket biofilm, but also in the presence of inflammation; they flourish, enabling their capacity to invade into host tissues and gain direct access into the circulation.6 As a consequence of this tissue-invasive property, not only are repeated bacteremias and endotoxemias characteristics of periodontal infections, there have also been reports of periodontal organisms colocalizing within atheromatous plaques, as detected by polymerase chain reaction methods.7 These studies suggest that periodontal pathogens may be present in atherosclerotic plaques where, like other infectious organisms such as Chlamydia pneumoniae, they may play a role in development and progression of atherosclerosis. Thus, the repeated exposure of the vasculature to these pathogens provides a clear opportunity for endothelial inflammatory activation and functional impairment.
Periodontitis increases systemic inflammation as measured by serum CRP and IL-6 Periodontitis appears to be one important infectious and inflammatory stressor that can increase the hepatic synthesis of CRP, which is a recognized predictor of acute MI and stroke. The most comprehensive study to date demonstrating an association of periodontitis with moderately elevated serum CRP concentration was reported by Slade and Ghezzi.8 In this study, a random sample of the US population (14 766 subjects) was interviewed in their homes and received periodontal exams at mobile examination centers. CRP was quantified by high-sensitivity (hs) enzyme-linked immunosorbent assay from peripheral blood samples and analyzed as a continuous variable and as the prevalence of elevated CRP (z10 mg/L). Dentate people with extensive periodontal disease (N10% of sites with periodontal pockets N4 mm) were associated with an increase of approximately one third in mean CRP and a
American Heart Journal June 2005
doubling in prevalence of elevated CRP compared with periodontally healthy people. Raised CRP levels among people with extensive periodontal disease persisted in multivariate analyses ( P b .01), adjusting for established risk factors for elevated CRP. Slade and Ghezzi9 also evaluated the association between periodontal disease and CRP levels in adults using the ARIC study. Periodontal disease was quantified as the percentage of periodontal sites with pocket depth of z4 mm. Serum hs-CRP concentration was quantified in milligrams per liter using a high-sensitivity enzyme-linked immunosorbent assay. In a multivariable linear regression model that controlled for age, sex, diabetes mellitus, cigarette use, and nonsteroidal anti-inflammatory drug use, the association of extensive periodontal pockets with hs-CRP concentration was modified by body mass index (BMI). For people with a BMI of 20, the model predicted a 2-fold difference in mean CRP concentration between periodontal pocket groups (7.5 vs 3.6 mg/L), but the difference decreased with increasing BMI and was negligible when BMI equaled 35. Thus, it appears that extensive periodontal disease and BMI are jointly associated with increased CRP levels in otherwise healthy middle-aged adults, suggesting the need for joint medical and periodontal diagnoses when evaluating sources of acute-phase response in some patients. In case-control studies, Ebersole and Machen,10 Loos and Hutter,11 Noack and Genco,12 and Amar et al13 showed that CRP levels were elevated in patients with periodontal disease as compared with periodontally healthy individuals. Loos and Hutter11 also showed that this elevation was not associated with seropositivity to C pneumoniae, cytomegalovirus, or Helicobacter pylori in subjects with periodontal disease. Amar et al13 showed an association of periodontal disease with both increased CRP and impaired endothelial function as measured by brachial flow-mediated dilation. Studies by Deliargyris et al14 demonstrated that patients with acute myocardial infection who had periodontal disease had significantly higher CRP levels than patients with acute MI who did not have periodontal disease (50.7 vs 30.7 mg/L, P b .001). In a multivariate linear regression analysis that included smoking, diabetes mellitus, and infarct size, a positive relationship was shown between the extent of periodontal disease and serum CRP levels. Periodontal disease emerged as a strong and independent predictor of elevated CRP levels after MI (r 2 = 0.33, P b .004). Some studies15,16 have demonstrated that mild and moderate periodontitis are both associated with incremental increases in serum IL-6, as well as CRP, but one study17 failed to see an association with increased IL-6 when examined in an elderly population. Interestingly, D’Aiuto et al16 have recently shown that serum IL-6 and CRP are higher among severe periodontitis patients carrying rare alleles for functional inflammatory
American Heart Journal Volume 149, Number 6
gene polymorphisms. Specifically, these investigators report increased serum IL-6 among periodontitis subjects with allele 2 for functional polymorphisms in IL-1A, tumor necrosis factor a, and IL-6 genes. Serum CRP levels were associated with allele 2 in the IL-1A and IL-6 genes. This finding is consistent with the concept that periodontal infectious exposure may be potentially more deleterious to cardiovascular health in the presence of a host genotype that favors a robust activation of the innate immune response.
Periodontal therapy decreases systemic inflammation and improves endothelial function Ebersole and Machen10 were the first to report an association between periodontal disease and increased levels of CRP, and their pilot data using periodontal treatment (scaling and root planing) and nonsteroidal anti-inflammatory drug treatment (flurbiprofen) also suggested that certain treatments can potentially lower serum CRP levels. A recent controlled clinical intervention study reported by D’Aiuto indicates that more traditional periodontal therapy (scaling and root planing alone) can significantly reduce not only CRP, but also serum IL-6 levels.16 These investigators report that among the 94 periodontitis subjects treated, significant reductions in serum IL-6 (median decrease 0.2 ng/L, 95% CI 0.1-0.4 ng/L, P b .001) and CRP (median decrease 0.5 mg/L, 95% CI 0.4-0.7, P b .0001) were observed 6 months after treatment. Although the median reductions in CRP were modest, patients who had a better response to periodontal therapy were also more likely to have decreases in their American Heart Association CRP risk category (OR 4.8, 95% CI 1.4-15.8) adjusting for age, sex, ethnicity, and smoking.18 Collectively, these data suggest that periodontal disease may be associated with mild increases in CRP (a point estimate increase of 2.7 mg/L, based upon data by Slade and Ghezzi9) and perhaps higher levels of serum IL-6. Increased serum IL-6 is mechanistically relevant to these findings, as it is not only a potent inflammatory inducer of hepatic CRP synthesis, but it is also an activator of endothelial inflammation. Thus, the IL-6 cytokinemia associated with periodontal disease may, in part, contribute to the observed association of impaired endothelial function, as measured by the hypoxia-stimulated nitric oxide– mediated hyperemia response. However, the findings by Slade and Ghezzi9 caution us, in that in an obese individual, periodontal therapy may not result in any decrease in CRP, perhaps a reflection of the linkages between obesity and increased serum IL-6. The report of Seinhost et al is significant because it provides the first evidence that treating periodontal disease results in a functional improvement in cardiovascular status.
Offenbacher and Beck 953
All of these studies are consistent with the concept that periodontal disease may be a previously underappreciated source of infectious and inflammatory vascular stress that has the potential to result in pathology of significant magnitude and prevalence. However, it is critical to emphasize that large, randomized, multicentered trials have not yet been conducted to definitively demonstrate the potential benefits of periodontal therapy to reduce the levels of CRP, or more importantly whether periodontal treatments reduce overall cardiovascular risk. What is encouraging from a health care perspective is that periodontal disease represents a potentially modifiable risk factor that is both preventable and treatable with predictable treatments that pose negligible risk. Considering that at the very least, periodontal therapy would improve oral health, we suggest that periodontal therapy as an integral component of preventive cardiology treatment is worthy of further study in both longitudinal clinical studies designed to test causality, as well as multicentered trials designed to evaluate the potential cardioprotective effects of periodontal treatment.
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