Periodontitis and arrhythmias: an emerging paradigm in cardiovascular medicine

Introduction

Periodontal disease, characterized as inflammation affecting the periodontal tissues and the underlying bone, is primarily initiated by the accumulation of dental plaque and calculus and has been increasingly recognized as more than just a localized oral disease.¹ According to WHO, periodontal disease affects 20-50% of the population globally with equal incidence among male and female populations.² Approximately 75% of adults in the United States are estimated to be affected by periodontal disease with 20-30% afflicted with a severe form of the disease.³ Growing research has uncovered a significant association between periodontitis and cardiovascular disease (CVD) that has potential implications on public health as a marker of increased morbidity. Major contributing factors include neglected dental appointments, dental misalignment, smoking, diabetes and insufficient dental hygiene practices.^4,5 The microorganisms associated with periodontal disease include aerobic bacteria such as Streptococcus sp. and Actinomyces sp. and anaerobic species such as Porphyromonas gingivalis, Prevotella intermedia, Peptostreptococcus spp., Fusobacterium sp., Treponema denticola, Eikenella corrodens, and Actinobacillus actinomycetemcomitans, which often coexist together.^6,7 Chronic bacterial activity, along with the production of toxins and metabolites, triggers an ongoing immune response, resulting in a gradual deterioration of periodontal attachment and premature tooth loss.⁶ which can initiate a cascade of pathological events that extend beyond the oral cavity, impacting multiple organ systems. As the infection disseminates below the gum line, the destructive impact on underlying bone and tissue ensues, enabling the infiltration of bacterial toxins into the bloodstream, thereby facilitating their access to crucial organs, including the heart.⁴ Ongoing periodontal disease and the subsequent systemic inflammation have been known to cause structural damage to the heart and promote fibrosis, leading to the perpetuation of arrhythmias.⁸ Patients with periodontitis exhibit a significantly higher incidence of arrhythmias, including atrial fibrillation, atrial tachycardia, ventricular tachycardia, and ventricular premature beats (93.6%).⁹ In recent years epidemiological studies have provided compelling evidence suggesting that poor dental health increases the risk of heart disease by 1.5-4 times and contributes to an elevated risk of cardiovascular mortality as well.⁴ Cardiovascular health studies have utilized an elevated inflammatory marker known as C-reactive protein (CRP) to establish an association between chronic periodontal inflammation and cardiovascular disease (CVD) which has been proven useful in predicting the future risk of heart disease in individuals with poor oral health, particularly those suffering from chronic periodontal disease.^10,11 The optimal care for individuals with periodontitis includes extensive management of comorbidities, efforts to reduce modifiable risk factors, oral health education, and routine oral examinations for patients with cardiovascular disease.¹² Research studies emphasizing the significant role of periodontal disease in escalating occurrence of fatal cardiovascular events seek to prioritize dental health among patients with cardiac conditions. Further research is needed to deduce whether interventions that aim to enhance oral health can possibly lower the risk of worsening cardiovascular disease (CVD).¹³ Although widespread bacteremia and damage to distant organs can be prevented by early treatment of periodontal disease, this is only advantageous to patients with mild-to-moderate and reversible forms of periodontitis.⁴ This review aims to explore the intricate relationship between periodontal disease and systemic health, particularly focusing on the potential implications and connections with cardiac arrhythmias.

Methods

Pathogenesis

Periodontitis is initiated by the colonization of pathogenic bacteria in the oral cavity, triggering an immune response resulting in release of proinflammatory cytokines, activation of immune cells and this local inflammatory process affects not only the periodontal tissues but also has systemic effects when inflammatory mediators and bacteria enter the bloodstream from daily life activities and oral interventions, promoting a proinflammatory state throughout the body.¹⁴ Periodontitis and cardiovascular diseases (CVD) share common risk factors including age, smoking, socioeconomic status, metabolic syndrome, and underlying pathophysiological processes.^12,15 The direct invasion of endothelium cells by periodontal pathogens, the indirect pathway, in which periodontal disease triggers a systemic inflammatory response, and shared genetic basis are three theories to explain the link between periodontal illness and cardiovascular disease.^16,17,18 Periodontal bacteria related to chronic inflammation have been found in atherosclerotic plaques and cardiovascular specimens containing thrombus tissues. These organisms can alter the barrier function of the vascular endothelium by a specific epithelial-mesenchymal transition, compromising the coherence of epithelial cells. This results in the formation of micro ulcerations, which facilitates the penetration of periodontal pathogens and virulence factors into the underlying connective tissue and exposed blood vessels.¹⁹ The exact mechanism of how direct invasion of the endothelial cells influences atherosclerosis is not clear. The presence of bacteria intracellularly is hypothesized to trigger foam cell formation and initiate secondary inflammation, leading to endothelial dysfunction and atherosclerosis.²⁰ The second mechanism involves the indirect pathway, where periodontal disease stimulates a systemic inflammatory response, resulting in elevated levels of inflammatory cytokines such as IL-1β, IL-6, IL-8, TNF-α, and monocyte chemoattractant protein-1. These cytokines can increase hepatic synthesis and secretion of plasma proteins like C-Reactive Protein (CRP) and fibrinogen.¹⁷ Additionally, bacterial components, such as lipopolysaccharide (LPS), associated with periodontitis can enter the circulation and induce a potent immune response. These factors contribute to atherosclerosis by affecting endothelial cells, lipid metabolism, and increasing oxidative stress.²¹ This systemic inflammatory response can also explain the association of periodontal disease with atrial fibrillation (AF). Multiple studies have demonstrated that inflammation can induce electrical and structural changes in the atrium, significantly contributing to the onset and progression of atrial fibrillation.²² Inflammatory factors such as C-reactive protein, interleukin-6, tumor necrosis factor-α, among others, can disrupt normal electrical activity in the pulmonary veins, shorten the atrial action potential, and interact with heat shock proteins or myeloperoxidase, thereby facilitating the development of atrial fibrosis.²³ Atrial fibrosis, a common pathological feature in AF, has been linked to periodontitis. In a study conducted in Japan involving 76 patients with AF, the relationship between gum disease and atrial fibrosis was investigated which found a positive correlation between various periodontal parameters, including Bleeding on Probing (BOP), Periodontal probing depth (PPD) of ≥4 mm, and periodontal inflamed surface area (PISA), with the presence of atrial fibrosis. These findings suggest that the chronic inflammation associated with periodontitis may contribute to the development and persistence of AF by promoting atrial fibrosis.⁸ The third mechanism involves shared genetic basis between periodontitis and cardiovascular disease and genome-wide association meta-analysis identified four PD loci, namely ANRIL/CDKN2B-AS1, PLG, CAMTA1/VAMP3, and VAMP8, which exhibited shared associations with coronary artery disease (CAD). Notably, the VAMP8 gene plays a crucial role in membrane vesicular trafficking and is susceptible to manipulation by pathogens, thereby impacting the host immune system. These genetic associations imply that the link between PD and CVD extends beyond shared environmental risk factors and involves common underlying genetic pathways^19,24 (Figure 1).

Figure 1. Summarizing potential hypothesized mechanisms linking periodontitis to the causation of cardiovascular diseases.

Discussion

Periodontitis is a chronic inflammatory condition affecting the tissues supporting teeth, including the gingiva, cementum, periodontal ligament, and alveolar bone.²⁵ It is characterized by a wide range of symptoms starting from gingival bleeding, bad breath, and alteration in gingival shape or appearance at the early stages of the disease to more severe symptoms like pain, pathological tooth mobility, periodontal abscesses, and tooth migration, due to advanced form of periodontitis often presenting as a periodontal abscess or pathological migration of anterior teeth resulting in esthetic problems.²⁶ Multiple clinical and radiographic parameters are used to diagnose periodontitis, such as inflammation, radiographic bone loss, probing depth, and clinical attachment loss. Patients having gingival recession or undergoing periodontal maintenance therapy but without any signs of inflammation, such as bleeding on probing and probing depths of ≤3 Mm, are diagnosed with a healthy but reduced periodontium, whereas patients with probing depths >3 mm and inflammation are often diagnosed with periodontitis.²⁷ Multiple epidemiological studies suggest that poor dental health increases the risk of cardiovascular mortality (Table 1). A meta-analysis by Harriet Larvin et al. of 32 longitudinal cohort studies revealed that cardiovascular disease (CVD) risk was significantly higher in individuals with Periodontal disease (PD) than those without PD, with a relative risk of 1.20 and a 95% confidence interval of 1.14-1.26.²⁸ Another study by Linda L Humphrey et al. found that different forms of periodontal disease, such as periodontitis, tooth loss, gingivitis, and bone loss, had summary relative risk estimates ranging from 1.24 (95% CI 1.01-1.51) to 1.34 (95% CI 1.10-1.63).³ These risk estimates remained consistent across subgroup analyses, including gender, outcome, study quality, and method of periodontal disease assessment. A retrospective study was carried out by Chen et al. for ten years, enrolling around 393,745 patients with PD and 393,745 non-PD individuals and, after adjusting for potential confounders, showed an increased risk of atrial fibrillation or flutter in the PD group compared with the non-PD group (HR, 1.31; 95% CI, 1.25-1.36).²⁹ Furthermore, a case-control study conducted by Im et al. reported that PD was identified as an independent predictor of major adverse cardiac events and arrhythmic events. After adjusting for various confounding factors, the study found that PD was associated with higher odds ratios for major adverse cardiac events (OR 17.78, 95% CI 3.46–91.34) and arrhythmic events (OR 9.19, 95% CI 1.24–67.96).⁹ Research carried out by Sahar Nader and Anwar T. Merchant has shown that individuals with periodontitis have higher plasma C-reactive protein (CRP) markers for cardiovascular disease levels than those without the condition. Treatment for periodontitis may lower CRP levels. In a study of 120 patients with severe periodontitis, participants were randomly assigned to community-based periodontal care or intensive treatment, including plaque removal and tooth extraction as necessary. Intensive treatment resulted in short-term inflammation and endothelial dysfunction. However, inflammatory markers were lower and endothelial function was improved 2 and 6 months after treatment compared to the control arm.³⁰ The Multi-Ethnic Study of Atherosclerosis (MESA) study enrolling 4,476 people aged 60 years or older without a known cardiovascular disease (CVD) history found that increase in carotid-artery intima and media thickness (CIMT) were directly associated with an increased risk of cerebrovascular events (CVE) and acute myocardial infarction (AMI).³¹ The Atherosclerosis Risk in Communities (ARIC) study, patients with moderate to severe forms of PD are more likely to have a CIMT 1 mm, with an odds ratio of 1.40 (1.17–1.67, 95% CI) and 2.09 (1.73– 2.53, 95% CI) respectively, compared to those without PD.³² The above studies show that healthcare practitioners must be informed about the link between periodontal disease and ASCVD due to the many patients affected by the two diseases. Therefore, some general clinical guidelines should be considered when treating these patients. These include proper diagnosis and treatment of periodontal disease, determining other risk factors for ASCVD and medical consultation, educating the patient on the periodontal association in ASCVD, and comprehensive periodontal therapy and lifestyle modification. Patients with a history of cardiovascular events should follow AHA guidelines for prophylaxis for dental procedures.³³ It is also important to recognize the severity of periodontal disease using a periodontal probe and performing radiographic assessments to measure clinical attachment levels and check for inflammation as it correlates with the risk of developing ASCVD.³⁴ Patients who are overweight/obese, smokers, diabetics, hypertensive, or have other risk factors for ASCVD should have routine medical assessments to rule out compounding factors. Alternatively, physicians should consider referring such patients to dentists to provide necessary periodontal treatments. As lifestyle habits increase the risk of periodontal disease and the development of cardiovascular disease, lifestyle changes such as changes in diet, engaging in regular exercise, and quitting smoking could positively affect oral and overall health.^35,36

Conclusion

Periodontal disease is an infection-based inflammatory condition due to bacterial biofilm accumulation adjacent to the gingiva. The systemic impact of the inflammation has yet to be fully understood, especially the heightened risk for cardiovascular disease and atrial fibrillation. With current epidemiological studies noting the presence of periodontal disease in up to one-third of the population globally, the intricate relationship between periodontal disease and its potential cardiovascular complications alongside shared risk factors such as age, smoking, socioeconomic status, and metabolic syndrome is crucial for future patient outcomes. This association between CVD and periodontal disease has been shown to follow three theorized mechanisms, the direct pathway, the indirect pathway, and shared genes. Furthermore, the current literature supports an increased risk of CVD events in patients with periodontal disease even after accounting for the patients’ demographics, study quality, and other confounding variables. Studies have also hypothesized that the increased incidence of CHD and other cardiac manifestations including arrhythmias in periodontal disease to be the result of structural damage to the heart and the promotion of fibrotic tissue. Although not all complications of periodontal disease are reversible, clinical measures such as plaque removal, tooth extractions, strict adherence to prophylactic AHA guidelines prior to dental procedures, and advancements in current treatment options can mitigate long-term inflammation and endothelial dysfunction. It is, therefore, essential for healthcare practitioners to have a better understanding of this relationship in order to provide comprehensive care to patients with cardiac conditions.