The Link between Periodontal Inflammation and Cardiovascular Disease: The Relative Role of the Host Response

The role of periodontal disease in the etiology of cardiovascular disease has recently received considerable attention. Previous studies have shown conflicting results as to whether periodontitis is associated with increased risk of cardiovascular disease, however, numerous recent studies have demonstrated that patients with chronic destructive periodontitis show evidence of systemic inflammation which can link chronic periodontitis and cardiovascular disease. Moreover, periodontitis and cardiovascular disease, share the same risk factors such as smoking, male gender, aging and diabetes. The aim of the current study was to evaluate whether such an association exists and to explore the mechanistic link between local and systemic inflammation and the relative role of the host response. The current study adds to the strong evidence for an association between periodontitis and cardiovascular disease, however, does not prove causation. Further research is needed to clarify the strength of association between cardiovascular disease and periodontal disease. The Link between Periodontal Inflammation and Cardiovascu lar Disease: The Relative Role of the Host Response. Biomed J Sci


Introduction
Periodontitis is chronic inflammatory diseases which is found worldwide and are among the most prevalent chronic infections in mankind. Severe forms of the disease can be found in 10-15% of the people and constitute a substantial inflammatory burden. People with advanced chronic periodontitis have been reported to have a significantly greater risk of developing cardiovascular disease (CVD), including atherosclerosis, myocardial infarction and stroke.
Premature death in men is known to be significantly related with coronary heart disease. More and more research is pointing toward a possible link between periodontal disease and increased risk of CVD [1]. Periodontal disease is initiated by bacteria particularly anaerobic gram-negative microorganisms such as Porphyromonas gingivalis (P. gingivalis), Prevotella intermedia, Tannerella forsythia and others in the subgingival plaque or biofilm, or their microbial products notably lipopolysaccharide (LPS) or endotoxin (a constituent of the cell wall of these gram-negative bacteria), inducing inflammation in the adjacent gingival and periodontal tissues. However, it is now widely accepted that the collagen and connective tissue destruction of the gingiva and periodontal ligament, and the loss of alveolar bone, is largely mediated by the host response [2,3].
LPS and other substances enter the gingival tissues, initiate and propagate immuno-inflammation, leading to production of elevated levels of proinflammatory cytokines. These and other inflammatory mediators stimulate production of matrix metalloproteinases (MMPs) which degrade the connective tissues of the gingiva and periodontal ligament; these and prostaglandins facilitate alveolar bone resorption [4]. Several studies have demonstrated that patients with chronic destructive periodontitis show evidence of systemic inflammation as indicated by elevations of C-reactive protein (CRP), fibrinogen, interleukin 6 (IL- 6), and other biomarkers in the circulation such as elevated cholesterol levels [5,6]. This systemic inflammation can link chronic periodontitis and CVD. In addition, periodontitis and certain systemic diseases, particularly cardiovascular disease, have the same risk factors such as tobacco smoking, male gender, race/ethnicity, stress, aging and diabetes [7].
The evidence is not clear yet, however, as stated by the American Academy of Periodontology, individuals with periodontal disease are nearly twice as likely to have coronary artery disease. In this regard one study found that the presence of common problems in the oral cavity, such as, gingivitis, caries, and missing teeth, were as good at predicting CVD disease as elevated cholesterol levels [8]. A link between periodontal disease and CVD may have important public health implications since both the periodontal disease and the CVD are highly prevalent in industrialized societies. Therefore, the link between periodontal disease and CVD is worth investigating because of its potential public health implications and because these studies could identify treatment strategies for periodontal disease that can interrupt this link. In addition, periodontal parameters including, bleeding on probing, Probing Depth (PD) and Clinical Attachment Level (CAL) may be a useful parameters of risk assessment for CVD in combination with other risk profile factors [9,10].

Materials and Methods
This study included 120 subjects (50 male and 70 female) aged 31 to 95 years. The Patients were randomly selected from Outpatient Department (OPD) of the National Heart Center in Benghazi/ Libya. Ethical committee approval was obtained from Faculty of Dentistry, University of Benghazi, the nature and intention of the study was explained to the patients and an informed consent from each patient was obtained. A questionnaire contains information about each single patient included (Name, age, sex, history of heart disease and heart surgery, and some of important laboratory test like; Triglycerides, CRP levels) were included. The diagnosis of all cases based up on patient's medical history that was evaluated by qualified physician and some other laboratory investigations.
Patients were excluded from the study if they had a known history of congenital heart disease.
A detailed case history which included information about the patient's overall medical status and oral status was recorded in a specially prepared form. Risk factors such as tobacco smoking, obesity, hypertension and diabetes mellitus was also recorded.

Statistical Analysis
The study used Statistical Package for Social Science (SPSS), version 18. Descriptive statistics including means, standard deviations, and percentages were used to summarize the results.

Results
A cross sectional study was undertaken with 120 participants to know the association between CVD and periodontal disease.

Discussion
Periodontal disease is not only the most common of all chronic inflammatory diseases known to mankind, and the major cause of tooth loss in adults, it has also been linked to various medical diseases particularly CVD such as atherosclerosis. The following discussion initially addresses the epidemiological associations between CVD and periodontal disease. This section is followed by clinical trials linking periodontal inflammation to CVD and biological mechanisms for this link.

Epidemiologic Studies
Numerous recent studies have investigated the question of CVD as risk factors for periodontal disease [11][12][13][14]. Seymour  direct bacterial damage to the endothelium and cross-reactivity or molecular mimicry between bacterial antigens and self-antigens" [15].
Although not all populations or studies show statistically significant associations between periodontal diseases and CVD, several of the studies, which were summarized by "meta-analyses", indicate significant associations even after adjustment of the traditional risk factors such as smoking, race, gender, obesity and blood lipids. Whether these links are causally associated or because of fundamental genetic or behavioural risk factors that are shared by both conditions remains uncertain [16].
Pussinen et al. found that coronary artery disease was more prevalent in patients with antibodies to P. gingivalis compared to those who were antibody-negative after he analysed the link between coronary disease and antibody levels in response to P.

Cardiovascular Disease
In addition to the proposed role of periodontal pathogens in the progression of CVD, it is increasingly being recognized that the inflammatory host response mounted in both the periodontal and in combination with other risk profile factors [28,29].
Recent studies have demonstrated that severe chronic periodontitis may also cause elevated serum levels of CRP [5,19,30].
In addition, some studies (but not all) have shown that periodontal treatment can reduce the serum levels of these biomarkers of systemic inflammation such as CRP [28,29,31]. The subjects were administered, in a double-blind placebocontrolled study, SDD bid (or look-like placebo) for 6 months.
He found that SDD treatment provided a significant reduction in MMP-9, HsCRP and IL-6 in the plasma of these patients compared to the placebo-treated subjects, indicating decreased systemic inflammation and decreased risk for future cardiac event without treating periopathogens [36]. It should be noted that Brown et al.

Biological Mechanisms
Many older medical studies have suggested a role in CVD for infection with a variety of organisms, such as Chlamydia pneumoniae, cytomegalovirus, and others. As the exact role of these infections in the development and progression of atherosclerosis is not completely understood, it is reasonable to suggest that DOI: 10.26717/BJSTR.2021. 33.005333 chronic periodontal infections could also take part in this multiple hit model, accelerating mechanisms involved in atherogenesis.

However, recent multi-institutional studies both in the USA and
Europe have found that long-term antimicrobial therapy had no effect on CVD [38][39][40][41], so in cardiology (if not in periodontics), this hypothesis has been overtaken by the "systemic inflammation" He concluded that infections at remote locations can modulate atherosclerotic events distantly [44]. In addition, Hayashi et al. demonstrated that by using in vivo MRI analysis together with ex vivo immunohistochemistry, P. gingivalis exposure results in an increase of atherosclerotic plaque accumulation in the arterys of ApoE deficient mice that is associated with the accumulation of lipids and macrophages. Furthermore, he also found increases in mean plaque area, lipids, and macrophage accumulation were prevented by immunization via a heat-killed preparation of P. gingivalis prior to challenge with live bacteria [45]. Gitlin and Loftin reported that P. gingivalis significantly increased atherosclerosis development in ApoE deficient mice when LPS was administered by chronic infusion for 28 days [3]. Although periodontal research has largely focused on the role of periopathogens, such as P. gingivalis, in the link between chronic periodontitis and CVD, as described earlier, cardiology research has largely moved away from this concept, and focused on systemic inflammation and lipid (e.g., cholesterol, triglyceride) abnormalities and elevated MMPs, as the driving force for CVD and as a target for therapeutic strategies (e.g., cholesterollowering statin, anti-inflammatory agents, resolving, etc).
However, in recent years, contribution of the host response, rather than periodontopathogens, may be the primary contributor to the link between periodontal disease and CVD. Cytokines produced locally, in inflamed periodontal tissues, such as IL-6 can be carried by the circulation to the liver where they induce the expression of acute phase proteins such as C-reactive protein, fibrinogen and haptoglobin resulting in the systemic inflammatory response [46].
CRP can form a complex with oxidized low-density lipoprotein (LDL) cholesterol, which, when phagocytosed by macrophages invading atheroscleromatous plaques can differentiate into foam cells [47,48]. The production of matrix metalloproteinases, for instance MMP-8 and MMP-9 by these inflammatory cells, can destroy the thin collagen ''cap'' that covers cholesterol-rich plaques lining the coronary arteries leading to plaque rupture, leading to thrombosis and acute myocardial infarction [48][49][50].
In summary, the results of the present study demonstrated a significant association between periodontal disease and CVD and indicated a near-100% incidence of periodontal disease in patients with CVD and have shown that almost all CVD patients exhibited moderate-severe chronic periodontitis. Although there was a positive correlation between periodontal disease and an increased risk for CVD, we cannot exclude, however, that general risk factors such as tobacco smoking, male gender, race/ethnicity, stress, aging and diabetes has an effect on the severity of periodontal disease and also considered risk factors for CVD. Periodontal disease was significantly correlated with CVD, therefore, periodontal parameters including, bleeding on probing (BOP), Probing Depth (PD) and Clinical Attachment Level (CAL) may be a useful parameters of risk assessment for CVD. A high serum level of high-sensitivity CRP (HsCRP) is a biomarker of systemic inflammation and significantly increases the risk for CVD [51,52] and might be useful as a method of risk assessment for CVD. However, CVD cannot be diagnosed with certainty by using HsCRP, therefore, periodontal parameters and HsCRP could be used in combination with other risk factors.
Our approach has been to consider the situation when the dentist detects severe periodontitis (PPD ≥7mm) and must decide whether this patient needs referral for specialist investigation.
From the literature we know that Severe periodontitis are strongly correlated with CVD, Therefore, they could be used in combination with other risk factors such as obesity, tobacco smoking, male gender, race/ethnicity, stress, advancing age, hypertension and in particular, diabetes and at least if there is one positive dental risk factor and one positive general risk factor the patient should be referred for consultation. Additional research is necessary to elucidate the strength of association between CVD and periodontal disease. A longitudinal assessment of systemic inflammatory markers and changes in periodontal parameters would be the preferred method for quantifying the association between CVD and periodontal disease. Nevertheless, the present study does fit well with in the findings of the existing literature.