Periodontitis and atherosclerotic cardiovascular disease

Abstract

Atherosclerotic cardiovascular disease (ASCVD) is a major global health concern linked to significant morbidity and mortality. Recent research has explored the relationship between ASCVD and periodontitis, a prevalent inflammatory oral condition. Epidemiological studies have suggested a strong association between periodontitis and ASCVD, even proposing that periodontal disease could be a modifiable risk factor for cardiovascular conditions. This review critically analyzes the current evidence for a potential causal role for periodontitis in ASCVD. While randomized controlled trials have demonstrated reductions in surrogate markers of cardiovascular risk following periodontal interventions, these studies remain inconclusive regarding their direct effects on cardiovascular events. Preclinical studies in animal models have suggested a potential causal relationship between periodontitis and ASCVD, proposing several biological mechanisms to explain this connection. These studies, however, are limited in their ability to definitively prove causality. The positive associations observed in epidemiological studies between periodontitis and ASCVD may also be influenced by various biases, such as confounding and collider stratification. Moreover, our systematic review of Mendelian randomization studies on the causal relationship between periodontitis and ASCVD found no evidence of a genetic causality, further challenging the causal hypothesis. This review underscores the need for further high-quality research clarifying the relationship between periodontitis and ASCVD to better guide clinical practice and public health policy.

Keywords: Atherosclerotic cardiovascular disease; Causal relationship; Mendelian randomization; Periodontitis; Systematic review.

Fig. 1

Biological mechanisms explaining a potential causal role for periodontitis in ASCVD. Periodontitis leads to bacteremia as oral bacteria enter the bloodstream through ulcerated periodontal pockets, especially following oral hygiene practices or clinical procedures. These bacteria can reach atherosclerotic plaques, where they exert harmful effects. Bacterial antigens that resemble host autoantigens may trigger an autoimmune response through molecular mimicry, contributing to plaque formation and progression by activating endothelial cells, monocytes, and T cells. Additionally, periodontal infections elevate systemic inflammatory mediators, including CRP, TNF-α, interleukins, and MMP-9, as well as thrombotic markers such as plasminogen activator inhibitor-1, fibrinogen, and vWF, thereby accelerating atherogenesis.

Fig. 2

Schematics comparing randomized controlled trials and Mendelian randomization studies. The left panel illustrates a randomized controlled trial (RCT) where individuals are randomly allocated to either a periodontitis induction group or a no-periodontitis group, followed by the observation of incident cardiovascular disease. The right panel depicts a Mendelian randomization approach, where individuals are naturally allocated according to the presence of alleles associated with periodontitis or other alleles, and the incidence of cardiovascular disease is observed. This method leverages genetic variants as proxies for the exposure (periodontitis), mimicking the randomization process of RCTs. SNP, single-nucleotide polymorphism.

Fig. 3

Directed acyclic graphs illustrating confounding bias. (A) A confounder (C) influences both the exposure (A) and the outcome (B). If the confounder is inadequately controlled, it can distort or obscure the association between the exposure and the outcome. (B) Common genetic or environmental factors may act as confounders, distorting the association between periodontitis and ASCVD.

Fig. 4

Directed acyclic graphs illustrating collider stratification bias. (A) Collider stratification bias occurs when a collider (C) is influenced by both the exposure (A) and the outcome (B) and is controlled for in the analysis. This can distort the association between A and B, altering the interpretation of the relationship between the exposure and the outcome. (B) When investigating the association between periodontitis (exposure) and carotid intima-media thickness (cIMT) (outcome), high-sensitivity C-reactive protein (hsCRP) acts as a collider because it is influenced by both periodontitis and an unknown genetic predisposition. This introduces bias in identifying an association between periodontitis and cIMT. (C) When investigating the association between periodontitis (exposure) and prevalent ASCVD (outcome), periodontitis may also act as a collider influenced by both statin use and an unknown genetic predisposition. This occurs because severe cases of periodontitis are selected due to the protective effects of statins, creating a spurious relationship between statin use and genetic predisposition. It may falsely appear that statin users with severe periodontitis have a higher genetic predisposition for inflammation, leading to an overestimation of the association between periodontitis and ASCVD.