Summary
Cardiovascular disease, such as atherosclerosis, is the main cause of mortality in developed countries. Most atherosclerosis risk factors have been identified and are treated, improving patient cardiovascular status and reducing mortality, but some remain unknown. Periodontal disease is generally defined as inflammatory disease initiated by accumulation of dental bacterial plaque, leading to the destruction of tissues that support the teeth. Severe forms have a high prevalence (15% of the population) and are associated with the presence of virulent pathogens such as Porphyromonas gingivalis. Epidemiological studies have shown that severe periodontal disease negatively influences cardiovascular status. The aim of this paper was to present a synthesis of the most recent biological data related to the link between periodontal and cardiovascular disease. The potential biological mechanisms involved in these two inflammatory diseases (bacteriological theory, inflammatory theory, immune theory) were developed. According to the observed positive effects of periodontal treatment on systemic conditions, the benefit of a reinforced collaboration between dentists and cardiologists was discussed, especially for patients at risk for cardiovascular disease.
Résumé
Les maladies cardiovasculaires sont une cause majeure de mortalité dans les pays développés. Malgré le fait que de nombreux facteurs de risque aient été mis en évidence et que leurs prises en charge aient réduit l’impact de ces pathologies sur la mortalité, certains de ces facteurs restent inconnus. Les maladies parodontales sont définies comme des pathologies inflammatoires induites par certaines bactéries buccales ayant comme effet la destruction des tissus de soutien dentaires. Les formes sévères de maladies parodontales ont une prévalence importante (15 % de la population) et sont associées à la présence de certaines bactéries spécialement virulentes tel Porphyromonas gingivalis . L’objectif de cet article est de présenter une synthèse des données biologiques relatives au lien entre maladies parodontales et pathologies cardiovasculaires. Les différents mécanismes biologiques impliqués (théorie bactérienne, théorie inflammatoire, théorie immunitaire) seront traités et l’effet bénéfique des traitements parodontaux sur certains paramètres biologiques seront discutés afin de proposer auxcardiologues et aux dentistes des modalités de collaboration, notamment concernant les patients présentant des facteurs de risque cardiovasculaires.
Introduction
Cardiovascular disease, including atherosclerosis, is a major public health concern. To ensure optimal treatment it is important for cardiologists to be aware of all of the potential risk factors for these pathologies. For more than 20 years it has been proposed that periodontal disease could influence the development of systemic disorders, increasing cardiovascular disease and diabetes severity as well as the rate of preterm birth . Since then, many clinical and experimental studies have investigated the link between atherosclerosis and periodontal disease, with variable conclusions . A recent meta-analysis from five prospective cohorts with coronary heart disease (CHD) concluded that individuals with periodontitis had a 1.14-time-higher risk of developing CHD than subjects without periodontitis. The case-control and cross-sectional studies included in this meta-analysis showed a greater association (odds ratio 2.2) . These data were confirmed by Mustapha et al. whose meta-analysis suggested a 1.75 average odds ratio . However, some studies consider that this relationship is relatively weak and argue that additional controls are needed to verify the relationship between these two diseases . Nevertheless, it is generally accepted that periodontal disease may contribute to cardiovascular events or stroke as shown by the recent consensus reports in dental and cardiology journals .
Periodontal disease
Periodontal disease is defined as inflammatory and infectious diseases of the gum and tooth-supporting tissues caused by long-term accumulation of dental biofilm and calculus . Periodontal disease can be classified as either gingivitis, which is superficial, reversible and relatively harmless, or as periodontitis, which is profound and irreversible . The main clinical signs of periodontitis are gingival bleeding, gingival retraction, long appearance of the teeth, tooth mobility, halitosis, abscess, periodontal pocket formation, bone loss, tooth mobility and, in the most severe cases, spontaneous tooth loss . Periodontitis is more prevalent in men and the peak of incidence is at around 60 years of age. The disease progresses slowly for decades, displaying successive phases of activity that are more or less destructive . Severe periodontitis affects almost 15–20% of the general population . Periodontitis is characterized by a strong inflammatory response and a rapid, profound and generalized destruction of periodontal tissues associated with the presence of virulent bacteria such as Porphyromonas gingivalis , Aggregatibacter actinomycetemcomitans and Treponema denticola . In addition to a notably impaired oral status, the negative influence of periodontal disease on general health is revealed in cases of severe periodontitis . The diagnosis of periodontitis is generally based on the clinical symptoms described above, and many studies based on self-report have shown that patients were able to evaluate correctly but grossly their periodontal status . However, the evaluation of periodontitis severity requires a specific clinical examination including periodontal pocket probing and radiological examinations performed by a periodontist or general dentist ( Fig. 1 ). X-ray bone level measurements reflect the history and severity of the periodontitis, but do not necessarily correlate with clinical parameters .
Periodontal treatments consist of the mechanical (dental hygiene, scaling and root planning, surgery) and chemical (antiseptic, antibiotic) suppression of periodontal biofilms. They efficiently decrease periodontal tissue inflammation and infection . Furthermore, they improve some systemic conditions (glycaemia, lipid metabolism, endothelial functions) . However, a large part of the French population is apparently not treated, especially patients at risk for systemic disease .
Cardiovascular disease
Atherosclerosis corresponds to the formation of atheromatous plaques, which are responsible for CHD, acute coronary syndromes (ACS) and ischaemic strokes, and represent approximately half of all cases of cardiovascular disease. They are the second highest cause of mortality in France. An annual rate of 120 000 ACS and strokes leads to 40 000 and 30 000 deaths, respectively. Men are more vulnerable than women and the highest incidence is at approximately 65 years of age .
The formation of an atheromatous plaque or atherosclerosis is a slow phenomenon, more or less reversible initially due to the transport and oxidation of lipids from low-density lipoprotein (LDL) on the arterial wall . Classically, various anatomopathological forms of atheromatous plaque have been defined (fatty streak, fibrous cap) . Recently, the notion of stable or unstable/vulnerable plaque has been proposed, to reflect the clinical consequences of atherosclerosis, such as ACS . ACS is triggered by rupture of the atherosclerotic plaque, and reduced blood flow leading to an ischaemic lesion of the myocardium . Plaque rupture is still not considered as a natural evolution of the atherosclerosis process, but depends on specific pathogenic pathways . The major risk factors for atherosclerosis are dyslipidaemia, high blood pressure, tobacco smoking, diabetes, socioeconomic stress, and advanced age, but around 10% of patients with cardiovascular disease have no conventional risk factors . With the exception of unstable angina, ACS and stroke, symptoms of atherosclerosis often remain subclinical, and its diagnosis is based initially on screening for the main risk factors. In order to evaluate the severity of atherosclerosis, and in addition to new non-invasive techniques, considerable research has been undertaken in the field of biochemical markers that are characteristic of the status of atheromatous plaques . Among these, inflammatory markers such as C-reactive protein (CRP) are routinely used to evaluate the evolution of atherosclerosis and cardiovascular risk. Indeed, the inflammatory response to trapped lipids in arteries plays an important (even predominant) role in the formation, and especially in the rupture, of the atherosclerotic plaque . The experimental (mice ApoE−/−) and the clinically observed (associated with diabetes, obesity, autoimmune disease, infection) modifications of the inflammatory response encourage the formation of atherosclerotic plaques .
Similar to periodontal disease, the treatment of atherosclerosis is based mainly on the underlying causes, including improved regimens of lifestyle and diet, hypolipidaemic drugs and corrective vascular surgery . Since 1980, a 20% decrease in ACS incidence has been observed in France, due to the development of cardiovascular disease prevention and treatments and adherence to guidelines . However, during the past 5 years, this decrease has declined, possibly due to the increasing incidence of diabetes and obesity. Furthermore, these data also highlight the limits of the current atherosclerosis treatments and the importance of the investigation of new risk factors .
Biological mechanisms
To explain the relationship between periodontal disease and cardiovascular disease, and in particular atherosclerosis, three major biological theories have been proposed: the bacteriological theory, the inflammatory theory and the immune theory .
The bacteriological theory
This theory refers to the concept of focal infection that shows an association between oral flora and systemic disease, especially endocarditis. It appears that some virulent periodontal pathogens such as P. gingivalis can disseminate from periodontal pockets to the general circulation and are found in the atheromatous plaque and in unaffected vessels . P. gingivalis produces numerous virulence factors including gingipains, lipopolysaccharide or fimbriae and may promote the development or evolution of atheromatous plaque through different pathways. These bacteria can activate endothelial cells through Toll-like receptor 4 and can induce apoptosis of endothelial cells through different pathways or disrupt adhesion structures including integrin β1-cadherin complexes . In vivo studies on apolipoprotein E-deficient mice, which eventually develop atherosclerosis, show that oral or systemic infection with P. gingivalis accelerates the development of atherosclerosis . It is important to notice that the amounts of some periodontal pathogens, such as P. gingivalis and A. actinomycetemcomitans, vary depending on the form of periodontitis . The deeper the periodontal pockets, the more important is the exchange surface between bacterial biofilms and blood circulation (15–20 cm 2 in the most severe cases) . Patients suffering from severe forms of periodontitis have higher concentrations of P. gingivalis and A. actinomycetemcomitans in periodontal pockets than patients presenting moderate forms . Many in vitro , in vivo , and clinical studies have suggested that higher concentrations of these bacteria may increase periodontal pathogen effects on endothelial cells and the evolution of atheromatous plaques ( Fig. 2 ).
