*2.2. Pathomechanism*

For this systematic review, six studies were found that addressed the potential pathomechanism that may be involved in the association and may explain how PD could induce or aggravate PAOD (see supplementary Table S1 for details). These studies sugges<sup>t</sup> at least three basic mechanisms (Figure 2): (1) Periodontal pathogenic bacteria were demonstrated to enter the bloodstream and to invade atherosclerotic lesions at damaged sites of the arterial wall [27,28]; (2) experimental data showed that inflammatory mediators, such as serum amyloid A and anti-inflammatory mediators, are released from the oral sites affected by PD into the bloodstream, thereby modulating systemic inflammation [29,30]; (3) it was demonstrated in patients with PD that autoimmunity to the host protein heat shock protein 60 (HSP60) resulted from the host immune response to the bacterial HSP60 homolog GroEL produced by *Phorphyromonas gingivalis* (the main oral pathogens involved in PD) [31].

**Figure 2.** Potential pathomechanism that may be involved in the association of PD and PAOD; (1) periodontal pathogenic bacteria enter the bloodstream, invade and damage the arterial wall; (2) release of inflammatory mediators into the bloodstream, such as serum amyloid A, interleukin-6 (IL-6), tumor necrosis factor α (TNFα), and C-reactive protein (CRP) causing a systemic inflammation that also damages the arterial wall; (3) autoimmunity to host proteins (i.e., heat shock protein 60, HSP60) resulting from the host immuno response to the bacterial proteins, such as the HSP60 homolog GroEL.

In a blinded randomized controlled trial, Li et al. [32] could show that treatment of PD lowered the number of circulating CD34+ cells relative to untreated controls. The reduction of circulating CD34+ cells correlated with the treatment-induced decrease in sites showing bleeding on probing and the number of periodontal pockets with a depth of ≥4 mm, suggesting that treatment of PD reduced the level of systemic inflammation. On the other hand, treatment of PD did not improve endothelial function in this study.
