"Gum bug, leave my heart alone!"--epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis

Abstract

Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of 'model' periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis.

Figure 1.

Schematic overview of potential mechanisms linking periodontal infections and endothelial dysfunction/incipient atherosclerosis. Vascular endothelial cells are invaded by fimbriated pathogens, e.g., P. gingivalis. These pathogens can persist and multiply intracellularly. Activation of Toll-like receptor 2 (TLR2) by fimbriated bacteria or LPS results in release of pro-inflammatory mediators and up-regulation of cell adhesion molecules. Monocytes are recruited by a gradient of chemotactic cytokines, such as MCP-1. Antibodies against bacterial heat-shock proteins, such as HSP60-related GroEL, auto-react with mammalian HSP60 expressed by activated endothelium, resulting in cell destruction. Further, P. gingivalis induces apoptosis of endothelial cells.

Figure 2.

Potential mechanisms linking periodontal infections and fatty-streak formation/plaque maturation. Monocytes activated by periodontal pathogens chemotactically migrate into the sub-endothelial space, and transform into macrophages and, subsequently, into foam cells after uptake of oxidized LDL. Apoptosis of LDL-laden macrophages results in accumulation of lipids in the sub-endothelial space. Furthermore, periodontal pathogens induce smooth-muscle-cell proliferation in the intima and neo-intima formation. Extracellular matrix build-up and extravasation of T-cells consummate the formation of a fibrous cap covering the plaque.

Figure 3.

Potential mechanisms linking periodontal infections to mature atherosclerotic plaques and plaque rupture. Pathogen-mediated in-plaque angiogenesis is a hallmark of plaque organization. Denudation of the fibrous cap and its pro-thrombotic components occurs after endothelial cell apoptosis mediated by whole periodontal pathogens, or anti-endothelial auto-antibodies. Plaque rupture is induced by pathogen-mediated extracellular matrix degradation by endothelial cells, plaque macrophages, T-cells, and plasma cells, leading to exposure of pro-thrombotic plaque components, and subsequent vessel occlusion.