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Page 10 of 18 Kozarov et al. Vessel Plus 2020;4:10 I http://dx.doi.org/10.20517/2574-1209.2019.31

of resolution as potential therapeutic agents for the management of inflammation has opened a new
promising area of research [131-134] .

Thus, in an established rabbit model of aortic plaque development, it was shown that oral/topical application
of a proresolution lipid mediator, Resolvin E1 (RvE1) diminished diet and periodontitis- induced aortic
atherogenesis. Importantly, RvE1 not only significantly attenuated the arterial inflammation; the treatment
also prevented periodontal inflammation (P < 0.05). In the absence of the latter, oral/topical administration
of RvE1 led to a reduction of the arterial plaque and a lower intima-media thickness ratio. RvE1 also
reduced the inflammatory cell infiltration in the animal model compared to non-treated controls (P <
0.001). In addition, local oral RvE1 application significantly diminished serum CRP levels (P < 0.05) [135,136] .

Multiple clinical investigations have also indicated a positive effect of periodontal disease treatment
on systemic inflammation. Periodontal therapy of periodontitis patients demonstrated significant
improvements in periodontal pocket depth, in brachial artery FMD and in serum IL-6. A trend toward
[137]
reduction in serum CRP has been reported in this study as well . Similarly, after non-surgical treatment
of periodontal patients, serum leptin, IL-6, and CRP levels were significantly decreased (mean ± SD before
and after, P value, respectively: leptin, 8.02 ± 5.5, 7.10 ± 4.4, P = 0.015; IL-6, 1.73 ± 1.02, 1.36 ± 0.73, P = 0.048;
[138]
and CRP, 802.0 ± 1065, 491.2 ± 479.3, P = 0.047) . Further, in a study of 49 patients with moderate to
advanced level of periodontitis, hsCRP and anti-P. gingivalis antibody levels were measured and the effect
of periodontitis treatment, including surgery and use of antibacterials, was analyzed on both markers. The
hsCRP levels and antibody titers were higher in the periodontitis patients than in the 40 periodontally
healthy control subjects. Furthermore, periodontal treatment significantly decreased he CRP levels and the
antibody titers (P < 0.005). A significant reduction of hs-CRP levels was communicated as a result of the
[56]
treatment in patients with hs-CRP levels > 1 mg/L (P < 0.005) .

More data supporting treatment were provided by the INVEST study of 420 participants (68 ± 8 years old)
at baseline and 3-year follow-up. The longitudinal carotid artery IMT progression was recorded.
Adjustments were made for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index,
systolic blood pressure, LDL cholesterol and HDL cholesterol. An attenuation of the IMT progression was
[139]
reported with improvement in clinical or microbial periodontal status .
A positive association has also been reported between severe periodontitis and oxidative stress [140] .
Introduction of periodontal therapy triggered a burst of inflammatory response before a progressive and
consistent reduction of systemic inflammation followed by an endothelial function improvement .
[141]
Furthermore, the reactive oxygen metabolites (d-ROMs) test values decreased and the biological
antioxidant potential test values increased in patients with chronic apical periodontitis after endodontic
therapy treatment. The oxidative stress levels in these patients exhibited a downtrend, returning to normal
in 90 days post treatment . Periodontal treatment however did not improve vasodilation in coronary
[142]
disease patients in a brief follow-up period, even though it maintained the titers of vascular inflammation
[143]
markers . An in-depth review on oxidative stress in periodontal disease, focusing on the relationship
between the local and systemic markers of oxidative stress and periodontal disease is in [144] . More
viewpoints on the subject of treatment are reviewed in [145,146] .

Finally, a meta-analysis was conducted investigating the literature on the association between carotid
IMT (c-IMT), FMD and periodontitis. The effect of periodontal treatment on carotid IMT and FMD was
assessed. Periodontal disease diagnosis was associated with a mean increase in c-IMT of 0.08 mm (95%CI:
0.07 to 0.09). The mean difference in FMD was 5.1% when compared to controls (95%CI: 2.08% to 8.11%). As
a consequence of periodontal treatment, a mean improvement on FMD of 6.64% (95%CI: 2.83% to 10.44%)
was observed between test and controls. This meta-analysis demonstrated an association between arterial