Systemic effects of periodontitis: lessons learned from research on atherosclerotic vascular disease and adverse pregnancy outcomes

Studies conducted over the past 25 years have focussed on the role of periodontitis, an inflammatory condition of microbial aetiology that destroys the tooth‐supporting tissues, as a systemic inflammatory stressor that can act as an independent risk factor of atherosclerotic vascular disease (AVSD) and adverse pregnancy outcomes (APOs). It has been suggested that periodontitis‐associated bacteraemias and systemic dissemination of inflammatory mediators produced in the periodontal tissues may result in systemic inflammation and endothelial dysfunction, and that bacteria of oral origin may translocate into the feto‐placental unit. Epidemiological studies largely support an association between periodontitis and ASVD/APOs, independently of known confounders; indeed, periodontitis has been shown to confer statistically significantly elevated risk for clinical events associated with ASVD and APOs in multivariable adjustments. On the other hand, intervention studies demonstrate that although periodontal therapy reduces systemic inflammation and improves endothelial function, it has no positive effect on the incidence of APOs. Studies of the effects of periodontal interventions on ASVD‐related clinical events are lacking. This review summarises key findings from mechanistic, association and intervention studies and attempts to reconcile the seemingly contradictory evidence that originates from different lines of investigation.     

Maternal chronic infection as a risk factor in preterm low birth weight infants: the link with periodontal infection

In the past decade, there has been mounting scientific evidence suggesting that periodontal disease may play an important role as a risk factor for adverse pregnancy outcomes. This article focuses on the definition, incidence, risk factors associated with preterm low birthweight infants (PLBW), the evidence linking chronic infections and PLBW, and the scientific evidence linking periodontal infections with adverse pregnancy outcomes. Additionally, this review summarizes the current epidemiological studies on the PLBW/infection relation and makes conclusions based on these results. Data from a limited number of studies available support the hypothesis that periodontal disease may act as a risk factor for PLBW infants. The fetal exposure to different periodontal pathogens needs to be confirmed, the mechanisms associated with the potential passage of periodontal bacteria across the placental barrier, and the efficacy of different periodontal treatments in reducing the risk for PLBW need to be studied further.     

Association of periodontal infections with atherosclerotic and pulmonary diseases

Chronic infections may influence the severity and/or course of a number of systemic diseases. Periodontal diseases are localized chronic inflammatory conditions of the gingiva and underlying bone and connective tissues induced by bacteria and bacterial products of dental plaque. This paper will discuss the evidence for the role of periodontal disease in the pathogenesis of 2 important systemic diseases, atherosclerosis and pulmonary infections. Both epidemiological and laboratory studies are reviewed to assess the biological basis for the association of periodontal infections and these important diseases. Several potential mechanisms by which periodontal diseases may influence these conditions are also discussed.     

Is There a Causal Link Between Periodontitis and Cardiovascular Disease? A Concise Review of Recent Findings

There is substantial evidence in support of an association between periodontitis and cardiovascular disease. The most important open question related to this association is causality. This article revisits the question of causality by reviewing intervention studies and systematic reviews and meta analyses published in the last 3 years. Where are we now in answering this question? Whilst systematic reviews and epidemiological studies continue to support an association between the diseases, intervention studies fall short in determining causality. There is a dearth of good-quality, blinded randomised control trials with cardiovascular disease outcomes. Most studies use surrogate markers/biomarkers for endpoints, and this is problematic as they may not be reflective of cardiovascular disease status. This review further highlights another issue with surrogate markers/biomarkers: the potential for collider bias. Ethical considerations surrounding nontreatment have led to calls for a well-annotated database containing in-depth dental health data. Finally, a relatively new and important risk factor for cardiovascular disease, clonal haematopoiesis of indeterminate potential, is discussed. Clonal haematopoiesis of indeterminate potential increases cardiovascular risk by more than 40%, and inflammation is a contributing factor. The impact of periodontal disease on this emerging risk factor has yet to be explored. Although the question of causality in the association between periodontal disease and cardiovascular disease remains unanswered, the importance of good oral health in maintaining good heart health is reiterated.     

The effect of initial treatment of periodontitis on systemic markers of inflammation and cardiovascular risk: a randomized controlled trial

Taylor B, Tofler G, Morel‐Kopp M‐C, Carey H, Carter T, Elliott M, Dailey C, Villata L, Ward C, Woodward M, Schenck K. The effect of initial treatment of periodontitis on systemic markers of inflammation and cardiovascular risk: a randomized controlled trial. Eur J Oral Sci 2010; 118: 350–356. © 2010 The Authors. Journal compilation © 2010 Eur J Oral Sci Observational studies indicate that chronic periodontal disease is associated with adverse cardiovascular outcomes. The aim of this study was to determine whether initial periodontal treatment has a beneficial effect on systemic markers of inflammation and cardiovascular risk. One hundred and thirty‐six adults with chronic periodontitis were allocated to either intervention or control groups in a 3‐month randomized controlled intervention study. The intervention group received initial periodontal treatment, whereas the control group did not receive that treatment until after the study. Blood levels of cardiovascular risk factors, and of hematological, inflammatory, and metabolic markers, were measured at the beginning and the end of the study, and differences were calculated. Fibrinogen level was the primary outcome measure. Data for 61 persons in the intervention group and for 64 persons in the control group were available for statistical analysis. Compared with the control group, the intervention group showed a non‐significant trend for a lower fibrinogen level. Significant increases in hemoglobin and hematocrit were seen after treatment, showing that initial periodontal treatment, a relatively simple and cost‐effective intervention, has systemic effects.     

General health risk of periodontal disease

The possibility that periodontal disease might influence the morbidity and mortality of systemic diseases constitutes a research topic of great current interest. Human periodontal disease is associated with a complex microbiota containing approximately 500 microbial taxa and various human viruses, many of which possess significant virulence potential. Actinobacillus actinomycetemcomitans, Porphyromonas gingivalis and other periodontopathic bacteria that are unique to the oral cavity and may disseminate to other body sites comprise the best‐documented form of dental focal infection. However, systemically healthy individuals seem to be at low risk of acquiring acute non‐oral diseases from direct infections by periodontal pathogens. Research data from various laboratories point to periodontal infections as a risk factor for chronic medical disorders, including cardiovascular disease, cerebrovascular accidents and low‐birth‐weight infants. However, recent epidemiological studies have failed to show a significant relationship between periodontal disease and cardiovascular disease. This review paper evaluates the current status of knowledge on dental focal infection and suggests avenues for further research into the topic of general health risks of periodontal disease.     

Periodontitis as a Risk Factor for Atherosclerosis

The relationship between poor oral health and systemic diseases has been increasingly recognized over the past two decades. Recent studies have suggested that periodontal disease caused by periodontopathic bacteria increases the risk of atherothrombotic disease. Atherosclerosis is an important component of coronary heart disease (CHD), which is the leading cause of death worldwide, including in Japan. Recent evidence has suggested that chronic inflammation plays a key role in promoting or accelerating atherosclerosis. Thus, periodontal disease has drawn considerable attention, and a number of epidemiological studies have shown that an association between the two diseases is highly likely. Several biologically plausible mechanisms have been presented to explain the association, such as bacteremia, elevated levels of inflammatory markers and the generation of cross-reactive immune responses by chronic infections. There is evidence demonstrating the direct invasion of periodontopathic bacteria into host cells, increased levels of high-sensitivity C-reactive protein and elevated levels of cross-reactive antibody between human heatshock protein 60 and GroEL of Porphyromonas gingivalis. In addition, several animal studies aimed at clarifying the effect of periodontopathic bacterial infection on atherogenesis have successfully shown the formation of atheromatous plaque and the elevation of systemic inflammatory markers. This review presents an update of the current understanding of the contribution of poor oral health to systemic diseases and discusses the possible mechanisms involved.     

Periodontal disease: associations with diabetes, glycemic control and complications

Objective:  This report reviews the evidence for adverse effects of diabetes on periodontal health and periodontal disease on glycemic control and complications of diabetes.
Design:  MEDLINE search of the English language literature identified primary research reports published on (a) relationships between diabetes and periodontal diseases since 2000 and (b) effects of periodontal infection on glycemic control and diabetes complications since 1960.
Results:  Observational studies provided consistent evidence of greater prevalence, severity, extent, or progression of at least one manifestation of periodontal disease in 13/17 reports reviewed. Treatment and longitudinal observational studies provided evidence to support periodontal infection having an adverse effect on glycemic control, although not all investigations reported an improvement in glycemic control after periodontal treatment. Additionally, evidence from three observational studies supported periodontal disease increasing the risk for diabetes complications and no published reports refuted the findings.
Conclusion:  The evidence reviewed supports diabetes having an adverse effect on periodontal health and periodontal infection having an adverse effect on glycemic control and incidence of diabetes complications. Further rigorous study is necessary to establish unequivocally that treating periodontal infections can contribute to glycemic control management and to the reduction of the burden of diabetes complications.     

Cardiovascular disease and periodontitis: an update on the associations and risk

Background: Associations between periodontitis and cardiovascular diseases have been recognized.
Material and Methods: New literature since the last European Workshop on Periodontology has been reviewed.
Results: The lack of reliable epidemiological data on disease prevalence makes an assessment of the associations and risks between periodontitis and cardiovascular diseases difficult. Two recent meta-analysis reports have identified associations between periodontitis and cardiovascular diseases (odds ratios: 1.1–2.2). Different surrogate markers for both disease entities, including serum biomarkers, have been investigated. Brachial artery flow-mediated dilatation, and carotid intima media thickness have in some studies been linked to periodontitis. Studies are needed to confirm early results of improvements of such surrogate markers following periodontal therapy. While intensive periodontal therapy may enhance inflammatory responses and impair vascular functions, studies are needed to assess the outcome of periodontal therapies in subjects with confirmed cardiovascular conditions. Tooth eradication may also reduce the systemic inflammatory burden of individuals with severe periodontitis. The role of confounders remain unclear.
Conclusions: Periodontitis may contribute to cardiovascular disease and stroke in susceptible subjects. Properly powered longitudinal case–control and intervention trials are needed to identify how periodontitis and periodontal interventions may have an impact on cardiovascular diseases.     

Update on general health risk of periodontal disease

Objectives : To review the potential of periodontal infections to cause nonoral diseases. Therapeutic recommendations are provided to help patients and dental practitioners prevent systemic complications from periodontal infections. Findings : Systemic diseases from oral bacteria are mostly caused by transient bacteraemias, which can occur spontaneously from dental foci of infection, from mastication, brushing, flossing or other daily manipulations, or from dental treatments. Examples of systemic infections that may involve oral microorganisms include infective endocarditis, aspiration pneumonia, HIV‐related disseminated candidiasis and cancrum oris, septicaemia associated with cancer chemotherapy and radiotherapy, necrotising faciitis and various other life‐threatening infections. Inflamed gingiva constitutes a significant reservoir for herpes viruses, which have the potential to cause serious systemic diseases in immunocompromised patients. Periodontal disease may also aggravate chronic insulin insensitivity and thus interfere with glycaemic control in diabetic patients. Controversy surrounds the involvement of periodontal infections in coronary heart disease. Conclusions : Cumulative evidence suggests that periodontal disease can be an important cause of morbidity and mortality of various systemic diseases, especially in individuals exhibiting compromised host defence. Maintaining a healthy dentition and periodontium by means of daily oral hygiene practice and regular professional care is the most effective way of preventing systemic diseases from oral infections.     

Viruses in periodontal disease - a review

The purpose of this review was to evaluate the evidence supporting the hypothesis that viral infection plays a role in the development of periodontitis. An involvement in periodontal diseases has been suspected specifically for human immunodeficiency virus (HIV) and herpes viruses. An association has been demonstrated between HIV infection and some distinct forms of periodontal infection, i.e. necrotizing lesions. Furthermore, reports of increased prevalence and severity of chronic periodontitis in HIV-positive subjects suggests that HIV infection predispose to chronic periodontitis. Several studies, most of them from the same research group, have demonstrated an association of herpesviruses with periodontal disease. Viral DNA have been detected in gingival tissue, gingival cervicular fluid (GCF) and subgingival plaque from periodontaly diseased sites. In addition markers of herpesviral activation have been demonstrated in the GCF from periodontal lesions. Active human cytomegalovirus (HCMV) replication in periodontal sites may suggest that HCMV re-activation triggers periodontal disease activity. Concerns regarding sampling, methods and interpretation cast doubts on the role of viruses as causes of periodontal disease.     

Periodontology/Oral Medicine: Periodontal infections and cardiovascular disease—how strong is the association?

In the past decade there has been renewed interest in the old hypothesis that infections increase the risk of developing cardiovascular disease and stroke. There is now a convincing body of evidence that atherosclerosis has a major inflammatory component and is much more than the simple vascular accumulation of lipids. Infectious agents that have been linked to an increased risk of coronary heart disease (CHD) include Chlamydia pneumoniae, Helicobacter pylori, cytomegalovirus, and herpesviruses. The concept has emerged that each of these agents is an independent risk factor for CHD and that common chronic infections are important. In addition, periodontal infections have also been implicated as one of several factors contributing to the development of CHD. Evidence supporting a causative role of chronic infections in CHD is largely circumstantial. However, the evidence is sufficiently strong to warrant further examination of the possible link between chronic infections and CHD. In this review the lines of evidence for a causative role of C. pneumoniae in the development of CHD are summarized and contrasted with the lines of evidence suggesting a periodontal infection--CHD association. If common or widespread chronic infections are truly important risk factors for CHD, it is unlikely that a single infection will be shown to be causative. It is likely that the entire microbial burden of the patient from several simultaneous chronic infections is more important (e.g., H. pylori-caused gastric ulcers + C. pneumoniae-caused bronchitis + periodontitis). Increased cooperation between cardiologists and periodontists will be required to determine if, and what, combinations of common chronic infections are important in the pathogenesis of CHD and stroke.     

The periodontal infection-systemic disease link: a review of the truth or myth

Observational studies indicate periodontal infections as a risk factor for systemic conditions like cardiovascular disease and preterm low birth weight. This paper reviews and argues the biological plausibility for a periodontal infection-systemic disease link and reviews the available experimental data from animal models and human intervention trials. Five principal lines of evidence can be used to explain the biological plausibility of a link. First, infection in general has been implicated in the pathogenesis of both atherosclerosis and preterm delivery. Periodontal infection secondly causes transient and low-grade bacteraemias and endotoxaemias in patients. Thirdly, periodontal infection promotes systemic inflammatory and immune responses that may play roles in disease. Periodontal pathogens express specific virulence factors that can affect atherogenic or parturition events. Lastly, periodontal pathogens have also been isolated from non-oral tissues like atheromatous plaques. Experimental data derived from rodent and pig models indicate that infection or bacteraemias with the periodontal pathogen, Porphyromonas gingivalis, can increase atheroma size or reduce litter weights as compared to controls. While human intervention data are lacking for patients at risk for cardiovascular disease, early data indicate that periodontal therapy administered to pregnant mothers with periodontitis can reduce the incidence of preterm low birth weight deliveries. Nevertheless, more and larger intervention trials are needed before we can fully accept periodontal infection as a true risk factor in the causal pathways of cardiovascular disease and preterm low birth weight.     

Periodontal treatment and its effects on glycemic control: a review of the evidence

Persisting poor glycemic control has been shown to be associated with the incidence and progression of diabetes-related complications. The bulk of oral health-related research has focused on the impact of diabetes on periodontal health, yet there are several lines of evidence to support the plausibility of the notion that periodontal infections contribute to problems with glycemic control. This article reviews the body of English-language literature containing reports of clinical research that has considered the relationship between treatment of periodontal diseases and improvement in glycemic control in humans. Although there is supportive clinical and epidemiologic evidence, equivocal and contrary evidence also exists. It is concluded from this review that the quantity, breadth, and strength of evidence-based knowledge are currently insufficient to establish periodontal therapy as influential in improving glycemic control in either type 1 or type 2 diabetes. Further rigorous, systematic study of the effects of treating periodontal infection on glycemic control is warranted.     

Periodontitis in cardiology--a clinical perspective

The association between ischemic cardiovascular disease and infectious disease is very dubious, and evidence points in several directions. Chronic periodontitis has been proposed as a potential risk factor based on many studies. A review of these studies demonstrates that the majority of them are retrospective epidemiological studies and therefore of little value in determining a possible association. New data seems to indicate an association between atherosclerosis and alveolar bone loss, thus indicating that a long-standing burden of infection is related to the slow process of atherosclerosis plaque buildup. Future secondary prevention studies will have to be performed to determine if periodontal therapy intervention results in decreased cardiovascular mortality or morbidity, proving a strong association between the two diseases.     

Biological foundation for periodontitis as a potential risk factor for atherosclerosis

OBJECTIVES: Links between periodontal diseases and systemic diseases have been well documented by epidemiological studies. Recently, research has shifted to elucidating the biologic mechanism for a causal relationship. One focus of interest is atherosclerosis, the underlying event of cardiovascular diseases due to its serious health impact. However, it is still not clear whether periodontopathic pathogens are truly etiologic agents or ubiquitous bystanders. This article reviews the current understanding about the molecular biological interactions between periodontal disease and atherosclerosis and the biological plausibility of periodontitis as a potential risk factor for cardiovascular disease. MATERIALS AND METHODS: The current literature regarding periodontal diseases and atherosclerosis and coronary vascular disease was searched using the Medline and PubMed databases. RESULTS: In vitro experiments and animal models are appropriate tools to investigate the biological interactions between periodontal disease and atherosclerosis at the cell molecular level. The concepts linking both pathologies refer to inflammatory response, immune responses, and hemostasis. In particular, Porphyromonas gingivalis appears to have unique, versatile pathogenic properties. Whether or not these findings from isolated cells or animal models are applicable in humans with genetic and environmental variations is yet to be determined. Likewise, the benefit from periodontal therapy on the development of atherosclerosis is unclear. Approaches targeting inflammatory and immune responses of periodontitis and atherosclerosis simultaneously are very intriguing. CONCLUSION: An emerging concept suggests that a pathogenic burden from different sources might overcome an individual threshold culminating in clinical sequela. P. gingivalis contributes directly and indirectly to atherosclerosis.     

Bidirectional interrelationships between diabetes and periodontal diseases: an epidemiologic perspective

This review evaluates evidence for a bidirectional relationship between diabetes and periodontal diseases. A comprehensive Medline search of the post-1960 English language literature was employed to identify primary research reports of relationships between diabetes and periodontal diseases. Reports included in the review on the adverse effects of diabetes on periodontal health (DM-->PD) were restricted to those comparing periodontal health in subjects with and without diabetes. Review of adverse affects of periodontal infection on glycemic control included reports of periodontal treatment studies and follow-up observational studies in which changes in glycemic control could be assessed. Observational studies reporting DM-->PD provided consistent evidence of greater prevalence, severity, extent, or progression of at least one manifestation of periodontal diseases in the large majority of reports (supportive evidence in 44/48 total reviewed; 37/41 cross-sectional and 7/7 cohort). Additionally, there were no studies reviewed with superior design features to refute this association. Treatment studies provided direct evidence to support periodontal infection having an adverse, yet modifiable, effect on glycemic control. However, not all investigations reported an improvement in glycemic control after periodontal treatment. Additional evidence to support the effect of severe periodontitis on increased risk for poorer glycemic control comes from 2 follow-up observational studies. The evidence reviewed supports viewing the relationship between diabetes and periodontal diseases as bidirectional. Further rigorous, systematic study is warranted to establish that treating periodontal infections can be influential in contributing to glycemic control management and possibly to the reduction of the burden of complications of diabetes mellitus.     

Association Between Periodontal Disease and Overweight and Obesity: A Systematic Review

Background: Periodontitis and obesity are among the most common chronic disorders affecting the world's populations, and recent reviews suggest a potential link between overweight/obesity and periodontitis. However, because of the scarcity of prospective evidence, previous reviews were primarily based on cross‐sectional studies, with only a few longitudinal or intervention studies included. This study's objective is to examine the time‐dependent association between obesity and periodontitis and how weight changes may affect the development of periodontitis in the general population. Therefore, longitudinal and experimental studies that assessed the association among overweight, obesity, weight gain, waist circumference, and periodontitis are reviewed. Methods: Intervention and longitudinal studies with overweight or obesity as exposure and periodontitis as outcome were searched through the platforms PubMed/Medline and Web of Knowledge. Results: Eight longitudinal and five intervention studies were included. Two of the longitudinal studies found a direct association between degree of overweight at baseline and subsequent risk of developing periodontitis, and a further three studies found a direct association between obesity and development of periodontitis among adults. Two intervention studies on the influence of obesity on periodontal treatment effects found that the response to non‐surgical periodontal treatment was better among lean than obese patients; the remaining three studies did not report treatment differences between obese and lean participants. Among the eight longitudinal studies, one study adjusted for C‐reactive protein (CRP) and biologic markers of inflammation such as CRP, interleukin‐6, and tumor necrosis factor‐α, and inflammation markers were analyzed separately in three of the five intervention studies. Conclusion: This systematic review suggests that overweight, obesity, weight gain, and increased waist circumference may be risk factors for development of periodontitis or worsening of periodontal measures.     

Cardiovascular diseases and periodontology

BACKGROUND: Cardiovascular diseases represent a widespread heterogeneous group of conditions that have significant morbidity and mortality. The various diseases and their treatments can have an impact upon the periodontium and the delivery of periodontal care. AIM: In this paper we consider three main topics and explore their relationship to the periodontist and the provision of periodontal treatment. METHOD: The areas reviewed include the effect of cardiovascular drugs on the periodontium and management of patients with periodontal diseases; the risk of infective endocarditis arising from periodontal procedures; the inter-relationship between periodontal disease and coronary artery disease. RESULTS AND CONCLUSIONS: Calcium-channel blockers and beta-adrenoceptor blockers cause gingival overgrowth and tooth demineralisation, respectively. Evidence suggests that stopping anticoagulant therapy prior to periodontal procedures is putting patients at a greater risk of thromboembolic disorders compared to the risk of prolonged bleeding. The relationship between dentistry and infective endocarditis remains a controversial issue. It would appear that spontaneous bacteraemia arising from a patient's oral hygiene practices is more likely to be the cause of endocarditis than one-off periodontal procedures. The efficacy of antibiotic prophylaxis is uncertain (and unlikely to be proven), and the risk of death from penicillin appears to be greater than the risk of death arising from infective endocarditis. Finally, the association between periodontal disease and coronary artery disease has been explored and there seem to be many issues with respect to data handling interpretation. Many putative mechanisms have been suggested; however, these only further highlight the need for intervention studies.     

The relationship of some negative events and psychological factors to periodontal disease in an adult Swedish population 50 to 80 years of age

Background: Clinical observations and epidemiological studies suggest that experiences of negative life events, especially those manifested as depression, may contribute to an increased susceptibility to periodontal disease. Objective: In the present study, the prevalence of some negative life events and psychological factors and their relation to periodontal disease were investigated. The sample consisted of individuals 50–80 years of age from an extensive cross‐sectional epidemiological study performed in 1993 in the city of Jönköping, Sweden. Method: 298 dentate individuals from the Jönköping study were randomly selected. Clinical and radiographic examinations included registration of the number of existing teeth, plaque index, gingival index, pocket depth, and alveolar bone loss. In addition, a questionnaire about socioeconomic status, life events, and psychological and stress‐related factors was used. Results: The results revealed that, in addition to the well‐documented periodontal disease risk factors such as increased age, oral hygiene status, and smoking, the loss of a spouse (being a widow or widower) and the personality trait of exercising extreme external control were also associated with severe periodontal disease. Conclusion: The findings support recent studies suggesting that traumatic life events such as the loss of a spouse may increase the risk for periodontal disease. Above all, the present results indicate that an individual's ability to cope with stressful stimuli (coping behavior), as measured by the beliefs of locus of control of reinforcements may play a role in the progression of periodontal disease.