Review
Association between Periodontal Disease and Arteriosclerosis-Related Diseases
2023 Volume 30 Issue 11 Pages 1517-1524
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2023 Volume 30 Issue 11 Pages 1517-1524
Periodontitis, a major inflammatory disease of the oral cavity that can cause low-grade systemic inflammation, has been suggested to influence the development of comorbidities. Multiple systemic inflammatory mechanisms are common in the development of periodontal disease and atherosclerosis. Observational studies conducted worldwide have reported that periodontal disease may independently influence the progression of atherosclerotic disease. However, there is still insufficient evidence to demonstrate the causal relationship. This review describes the association between periodontal disease and arteriosclerosis-related diseases with the latest findings.
Periodontal disease has a very high prevalence globally. In the early stages of this disease, few subjective symptoms occur. Thus, there are many cases in which the patient’s condition worsens as no therapeutic intervention is provided. Periodontal disease is a chronic inflammatory disease caused by infection with periodontal pathogens, such as the gram-negative bacillus Porphyromonas gingivalis (P. gingivalis). Due to poor oral hygiene, biofilm forms in the gingival sulcus, and periodontal disease develops and progresses. The main virulence factors of periodontal pathogens such as protease and endotoxin act on monocytes, macrophages, gingival fibroblasts, etc. in the periodontal tissue. These cells secrete inflammatory mediators, such as interleukin-1β (IL-1β), IL-6, IL-8, prostaglandin E2, tumor necrosis factor-α (TNF-α), and matrix metalloproteinases. These cytokines induce inflammatory response and cell injury through a complex cytokine network, leading to tissue destruction (Fig.1). Destruction of the periodontal tissue deepens the gingival sulcus to form a periodontal pocket. The depth of the periodontal pocket is an indicator of the degree of destruction of the periodontal tissue, and a periodontal pocket of 6 mm or more is a measure of severe periodontitis. Assuming that patients with periodontal disease have periodontal pockets of 5–6 mm on all 28 teeth, inflammatory lesions with a surface area of approximately 72 cm2 are chronically present in vivo1). It has been shown that periodontal disease is not only a local inflammatory disease of the oral cavity but is also associated with various systemic diseases such as diabetes, hypertension, and obesity2, 3). As Mattila et al. reported an association between the incidence of myocardial infarction and oral health4), the association between periodontal and cardiovascular diseases has gradually gained attention.
Cells in periodontal tissue secrete various types of inflammatory mediators, inducing inflammatory response and cell injury, leading to tissue destruction
Approximately 20 years ago, a positive correlation between serum antibody titers against the periodontal pathogen P. gingivalis and high-sensitivity C-reactive protein (hs-CRP) levels has been observed in patients with diabetes5). The same research group also found a marked increase in carotid artery thickening in nonobese patients with diabetes and high antibody titers6). These results indicate that enhanced systemic inflammation levels associated with diabetes and periodontal disease increase the risk of cardiovascular disease development. Observational studies conducted worldwide have reported that periodontal disease may independently influence the progression of atherosclerotic disease. However, there is still insufficient evidence to demonstrate the causal relationship7). This review aims to discuss the association between periodontal disease and arteriosclerosis-related diseases mainly based on recent findings.
Recent Findings from Clinical StudiesIt has been suggested that the combination of obesity and periodontitis amplifies inflammation to levels that affect the whole body through the adipose tissue3). Kanno et al. reported that the severity of periodontitis was significantly correlated with pericardial adipose tissue volume, which has been associated with progressive cardiovascular diseases8). Recent studies have also shown that the progression of periodontal disease, degree of inflammation correlated with the thickening of the common carotid artery, and presence of carotid artery atherosclerotic plaque9-12). Other researchers reported that the degree of periodontal inflammation correlated with the risk of developing future cardiovascular disease events13, 14). With a 13-year follow-up, Tiensripojamarn et al. showed that severe periodontitis was associated with increased incidence of coronary heart disease, independent of established cardiovascular risk factors15). They observed that the length of follow-up period is important in prospective studies of time-dependent diseases/events. Independent associations have also been reported between the prevalence and severity of periodontal disease and carotid plaque size, suggesting that periodontal therapy helps prevent cardiovascular disease16).
Van Dyke et al. used positron emission tomography/computed tomography with 2-deoxy-2-[fluorine-18) fluoro-D-glucose (18F-FDG-PET/CT) to identify sites of inflammatory activity and showed that periodontal tissue inflammation was associated with an increased risk of subsequent cardiovascular events13). In addition, 18F-FDG-PET/CT analysis showed a correlation between gingival inflammation and bone marrow hematopoietic activity. These results suggest that periodontal disease is associated with arterial inflammation through enhancement of the hematopoietic arterial axis17).
Pavlic et al. reported that in patients with periodontitis with moderate or severe atherosclerosis, the detection rate of P. gingivalis was 26.7% in the carotid arteries and 39.3% in the coronary arteries18). It has also been shown that the presence of circulating periodontal pathogens was significantly correlated with the incidence of acute myocardial infarction and severity of coronary artery lesions19) and that there was a difference in the periodontal pathogens present in the blood of patients with/without coronary artery disease20). However, the potential pathogenic role of bacteria at the site of atheromatous lesions remains unclear. It is important to verify by what mechanism and to what extent the bacteria at the lesion site affect atherogenesis.
The increase in the number of reports stating that serum CRP, IL-6, and low-density lipoprotein (LDL) cholesterol, which are risk markers for atherosclerosis, are elevated in patients with periodontal disease, and periodontal treatment improves these levels is not recent21-23). Several recent studies have shown that periodontal therapy improves cardiovascular disease risk markers in the short term24-26). Caribé et al. reported that periodontal therapy reduced the blood concentration of mannose-binding lectin, a possible indicator of atherosclerotic plaque instability27). In a 16.8-year follow-up study of subjects aged 20–85 years (N=8,999), patients with poor prognosis after periodontal therapy were found to have 1.28-fold higher incidence of cardiovascular disease, including atherosclerosis, than those with good prognosis28). Periodontal therapy has also been suggested to help prevent the development of coronary heart disease in some patients29). On the contrary, it had been reported that periodontal therapy had no significant effect on atheromatous lesions or vascular inflammation30, 31). A previous study showed that obesity affects the efficacy of periodontal therapy in patients with diabetes and severe periodontitis. Subjects with a body mass index (BMI) of about 25 kg/m2 had significantly higher hs-CRP levels at baseline than those with a BMI of about 23 kg/m2. After periodontal treatment, subjects with a BMI of about 25 kg/m2 had improved hs-CRP and HbA1c levels. Contrarily, those with a BMI of approximately 23 kg/m2 showed no significant change in these levels after the treatment32). Because obesity promotes systemic inflammation, it should be considered that differences in the degree of obesity between subjects are likely to affect results, particularly inflammatory markers. Therefore, it cannot be said that all patients with atherosclerotic lesions are equally affected by periodontal therapy. Put another way, it can be said that there is certainly a patient population for whom this treatment is effective. This study also showed that in patients with severe periodontitis with elevated hs-CRP levels, periodontal therapy may inhibit the progression of atherosclerosis by reducing inflammation levels.
Lifestyle can influence the augmentation of important risk factors in the association between periodontitis and atherosclerosis. Several studies have been performed on the relationship between carotid intima-media thickness or area and periodontitis after adjusting for or excluding confounding factors12, 15, 27), but the accumulation of such data is still insufficient. It is necessary to verify and accumulate evidence by appropriately adjusting for confounding factors.
Mechanism by which Periodontal Disease Affects ArteriosclerosisTo elucidate the mechanism by which periodontal disease affects arteriosclerosis, many verifications with animal models or in vitro have been so far. Periodontal bacteria or their metabolites can directly act on cells composing blood vessels. Furthermore, inflammatory response in periodontitis may indirectly contribute to the promotion of atherosclerosis by affecting systemic inflammatory mediators, elevated lipid levels, and the immune system (Fig.2). Several mechanisms have been postulated based on recent validations.
Possible mechanisms by which periodontal disease affects arteriosclerosis
The scavenger receptor lectin-like oxidized LDL receptor-1 (LOX-1) plays an important role in P. gingivalis-induced migration and adhesion of macrophages to vascular endothelial cells33). Wu et al. demonstrated that the P. gingivalis-induced macrophage migration inhibitory factor interacts with the CD74/CXCR4 receptor complex and may serve as a key regulator of monocyte–endothelial cell adhesion34). Other researchers have reported that gingipains and outer-membrane vesicles of P. gingivalis mediated increased vascular permeability via a mechanism that involves proteolytic cleavage of platelet endothelial cell adhesion molecule 1 (PECAM-1)35, 36). Farrugia et al. showed that Fusobacterium nucleatum (F. nucleatum) mediated vascular endothelial damage and increased permeability37). P. gingivalis has also been suggested to activate Rho/Rho-associated protein kinase 1 pathway and promote mitochondrial dysfunction through dynamin-related protein 1 (Drp1)-dependent mitochondrial fission in endothelial cells, exacerbating atherosclerosis38, 39).
It has been suggested that the systemic effects of periodontitis may result from the efflux of inflammatory cytokines and other mediators from the periodontal tissue into the circulatory system40). To elucidate the relationship between periodontitis and arteriosclerosis, many studies have been conducted using arteriosclerosis model mice with experimental periodontitis. Several possible mechanisms have been presented.
Validation using apolipoprotein E-deficient (ApoE−/−) mice with experimental periodontitis suggested that hyperlipidemia is essential for atherosclerosis induced by periodontitis41). Zhou et al. reported that F. nucleatum promoted glycolysis and lipogenesis through phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin signaling in hepatocytes, thereby impairing lipid metabolism and exacerbating atherosclerosis42). It has also been shown that F. nucleatum exacerbates atherosclerosis through abnormal proinflammatory responses and lipid metabolism in macrophages43). Suh et al. demonstrated the mechanism by which rosuvastatin, which lowers LDL cholesterol level, suppresses atherosclerosis caused by periodontitis from experiments in ApoE−/−-ligated mice and in vitro44). CD36-mediated lipoprotein uptake and accumulation by arterial macrophages is a key feature of atherosclerosis. Foaming of macrophages caused by periodontal disease bacteria has also been reported to affect the progression of arteriosclerosis. P. gingivalis increases the expression of CD36 and fatty acid-binding protein 4 (FABP4) on macrophages, promoting the internalization of oxidized LDL (o-LDL) and intracellular conversion of o-LDL to cholesterol crystals45, 46). Rho et al. showed that changes in Ca2＋ and reactive oxygen species (ROS) signaling and lipid homeostasis dysregulation by periodontal pathogens are important for macrophage foaming47). It has been suggested that lysosomal integral membrane protein 2, a member of the CD36 superfamily, is involved in foam cell formation promoted by P. gingivalis48). The exoprotein of F. nucleatum, D-galactose-binding protein (Gbp), has also been reported to induce foaming of macrophages49).
Mechanisms associated with effects on the immune system have been suggested. Host immune responses in susceptible individuals promote vascular inflammation. When the host is attacked by periodontal bacteria, it can exhibit a highly inflammatory monocyte phenotype and abnormally release large amounts of proinflammatory substances50). Individuals with this monocyte phenotype are at an increased risk of suffering from periodontitis and endothelial dysfunction51). The Th17/Treg balance is disrupted in atherosclerosis52). Yang et al. reported that P. gingivalis reduces the activity of indoleamine 2,3 dioxygenase (IDO), a potential regulator of peripheral Th17/Treg balance, further promoting Th17/Treg imbalance and leading to the development of atherosclerosis53). A recent noteworthy study proposed that periodontitis induces maladaptive trained myelopoiesis54). A trained phenotype induced by periodontitis is transferred to naive recipients through bone marrow transplantation and has been shown to increase inflammatory reactivity and disease severity when exposed to inflammatory arthritis54). Noz et al. applied trained immunity to show that monocytes/macrophages construct immunological memory after encountering pathogens, resulting in a persistent hyper-responsive phenotype55). P. gingivalis induces trained immunity in human monocytes in terms of enhanced cytokine production55). Periodontitis-associated systemic inflammation may induce trained immunity in bone marrow hematopoietic stem and progenitor cells and promote the generation of myeloid cells with hyper-responsive phenotype. Maladaptive training of hematopoietic progenitor cells may lead to an increased risk of cardiovascular complications in patients with inflammatory diseases, such as periodontitis56, 57). Wu et al. presented that cyclic diadenylate monophosphate, which can modulate trained immunity, regulates microbiota balance, thus preventing the effects of P. gingivalis infection on atherosclerosis58).
Heat-shock proteins (HSPs) are highly immunogenic despite the presence of a high level of sequence conservation between bacteria and mammals. A link between HSPs and atherosclerosis has been suggested59). Experimental models have demonstrated that immunization of normochloremic animals with bacterial HSP60 causes atherosclerosis and that elevated blood cholesterol levels can exacerbate this process60). Joo et al. proposed that peptide 19 from P. gingivalis HSP60 has a distinct ability to induce native LDL oxidation in the pathogenesis of atherosclerosis61). The chaperonin GroEL, which belongs to the HSP60 family, is produced by P. gingivalis. Recently, it has been reported that sublingual immunization with P. gingivalis GroEL62) or nasal immunization with peptide 14, a peptide derived from P. gingivalis HSP60 63), inhibits atherosclerotic plaque formation. However, there are few studies on the relationship between P. gingivalis-associated vaccines and atherosclerosis, and the mechanism of action is not fully understood and thus needs further investigation.
The effects of oxidative stress (OS) have also attracted attention. OS is an important factor causing endothelial dysfunction. Excessive ROS accumulation interferes with the nitric oxide (NO) signaling pathway, thereby reducing NO bioavailability, causing endothelial dysfunction, and reducing endothelium-dependent relaxation64). Periodontal disease is strongly associated with increased ROS synthesis in the endothelium and decreased NO bioavailability. Xie et al. showed that brain and muscle Arnt-like protein 1 (BMAL1) downregulation and its associated circadian clock disturbance aggravate P. gingivalis-induced atherosclerosis by elevating OS formation65).
The oral microbiota influences the gut microbiota and may contribute to various systemic diseases66). A link between intestinal dysbiosis and atherosclerosis has also been suggested67). Therefore, effects mediated by intestinal bacteria that link periodontitis and atherosclerosis are also conceivable. Arimatsu et al. reported that dysbiosis of the gut microbiota is induced in mice orally administered with P. gingivalis68). Trimethylamine N-oxide (TMAO), a metabolite of gut flora, has been shown to be a promising indicator of atherosclerosis69). Xiao et al. showed that experimental periodontitis in ApoE−/− mice induced gut dysbiosis and increase in TMAO70). In addition, it has been presented that the administration of lactic acid bacteria suppresses the progression of arteriosclerosis by suppressing changes in the intestinal flora caused by periodontal pathogens71).
Low-grade inflammation of periodontitis can affect glucose metabolism. Ilievski et al. demonstrated that mice orally administered with P. gingivalis developed glucose intolerance, insulin resistance, and hyperinsulinemia72). Periodontitis-derived virulence factors have also been implicated in visceral adipose tissue insulin resistance through activation of infiltrated macrophages in adipose tissue and subsequent release of inflammatory factors such as TNF-α and IL-1β, especially in the obese state73-75). These inflammatory factors reduce the activity of glucose transporter 4 and downregulate insulin receptor substrate expression in adipocytes75). Glucose intolerance and insulin resistance are significant risk factors for atherosclerosis, and the presence of periodontitis may indirectly promote atherosclerosis by aggravating these risk factors.
Multiple systemic inflammatory mechanisms are common in the development of periodontal disease and atherosclerosis. Numerous reports have shown that periodontal therapy reduces serum inflammatory mediators, improves lipid profiles, and reduces the risk factors for cardiovascular disease, supporting the link between both diseases. However, the evidence is still insufficient to determine a causal link between the two diseases. Further studies in vivo and in vitro, especially well-designed long-term follow-up studies, and accumulating evidence are warranted.
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI under Grant Numbers JP22K09968.
The author declares there is no conflict of interest related to this work.
