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Kozarov et al. Vessel Plus 2020;4:10 I http://dx.doi.org/10.20517/2574-1209.2019.31 Page 5 of 18

2.50, P = 0.077) for prevalent coronary disease. The combined antibody response was directly associated
with prevalent CHD (P = 0.046) and inversely associated with the concentration of serum high-density
lipoprotein (HDL) cholesterol (P = 0.050). This demonstrated that serum antibodies to major periodontal
[50]
bacteria were associated with CHD .
In addition, the same group demonstrated that systemic exposure to P. gingivalis predicts incident stroke.
Investigating seropositive subjects, it was found that they had a multivariate odds ratio of 1.6 (95%CI: 1.0 to
2.6) for stroke, compared with the seronegative subjects. Additionally, patients with a history of stroke or
CHD at baseline contained more often P. gingivalis IgA than the controls, 79.7% vs. 70.2%. The seropositive
[51]
subjects had an odds ratio of 2.6 (1.0 to 7.0) for secondary stroke, compared with the seronegative . In the
CVD-free individuals (n = 893), systemic exposure to P. gingivalis increased the risk of stroke as follows:
compared to seronegative subjects, men and women that were IgG-seropositive for P. gingivalis presented
a multivariate OR (95%CI) of 1.63 (1.06 to 2.50) and 2.30 (1.39 to 3.78) for stroke, respectively. Interestingly,
higher OR was observed in males, who had never smoked. Compared to seronegative men, P. gingivalis
IgA-seropositive men had a OR of 3.31 (1.31 to 8.40, P = 0.012) for stroke. There was no association found
between antibody titers to A. actinomycetemcomitans and stroke, suggesting that the systemic exposure
[52]
specifically to P. gingivalis may contribute to incident stroke .
These authors also presented data demonstrating that periodontitis also causes mild changes in HDL
metabolism. These changes appear to be less severe than those occurring during the acute-phase
response. Thus, periodontitis may reduce the anti-atherogenic properties of HDL, increasing the risk for
CHD. Importantly, the HDL-mediated cholesterol efflux improved after periodontal treatment. More
interestingly, this increase was significant (P < 0.05) among those patients whose CRP titers decreased (53.7%
[53]
reduction, P = 0.015) and who were PCR-positive for A. actinomycetemcomitans .

In comparison, P. gingivalis induces HDL oxidation, impairing the atheroprotective function of HDL.
P gingivalis likely makes it proatherogenic by raising a proinflammatory response via interaction with
[54]
monocytes and macrophages . Overall, the presence of A. actinomycetemcomitans and P. gingivalis, major
causative organisms in periodontitis was shown to be the strongest determinant of the systemic antibody
[55]
response to these pathogens .
Concerning serum antibodies, in coronary disease as well as in periodontal disease patients the antibody
titers against P. gingivalis were the most prevalent. Hs-CRP test levels and antibody titers to P. gingivalis
have been reported to be higher in periodontitis patients than in control subjects . Interestingly, while
[56]
periodontal patients were seropositive for both studied P. gingivalis strains, FDC381 and Su63, higher
antibody titers to P. gingivalis Su63 only was observed in coronary disease patients. This finding indicates
that specific genomic virulence determinants present in particular P. gingivalis strains may affect
[57]
atherogenesis .
The association of P. gingivalis antibodies with mortality is however non-linear. In a specific study,
mortality was highest for those just above the median anti-P. gingivalis response and a reduced risk was
present among those with low or high titers of the antibody , suggesting that the efficiency of the immune
[58]
response itself may be the key to control of the infection.

In a first 27-year long-term study of association of chronic oral infections in childhood with subclinical
carotid atherosclerosis in adulthood in 755 participants, the infections were associated with adulthood
IMT. The relative risk (RR) found was 1.95 (95%CI), especially elevated in boys, RR 2.25 (95%CI). The
associations were independent of cardiovascular risk factors . Specifically, the salivary IgA antibody levels
[59]
to malondialdehyde acetaldehyde-modified low-density lipoprotein (MAA-LDL), Rgp44 (gingipain A