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Kozarov et al. Vessel Plus 2020;4:10 I http://dx.doi.org/10.20517/2574-1209.2019.31 Page 3 of 18

Infection is an understudied contributing factor in vascular inflammation. Nevertheless, infectious
component as a risk factor is supported by an abundance of epidemiological evidence [20,21] and animal
models. Multiple independent pathways of evidence already pinpoint inflammation as a key regulatory
process that links multiple risk factors for atherosclerosis and its complications with altered arterial
[22]
biology . Vascular infection due to transient bacteremia, from leaky guts or periodontal lesions alike, can
lead to persistent inflammation, including one due to an intracellular bacterial “privileged niche”. Indeed,
blood levels of inflammation markers (e.g., C-reactive protein, CRP) have been associated with vascular
[23]
risk factors and the prevalence and incidence of atherothrombotic CVD . Consequently, hsCRP (a high
[24]
sensitivity CRP test) is an important prognostic factor for atherosclerosis .

More critical evidence can be found in the Northern Manhattan study of stroke incidence and prognosis.
This prospective cohort study (1625 participants, mean age 68.5 ± 10.1 years; 64.9% women) demonstrated
that infectious burden is associated with established measure of risk of stroke, carotid plaque intima-
media thickness [25-27] . Interestingly, a measure of infectious burden associated with risk of atherosclerosis
and stroke was independently associated in this study with cognitive performance. This demonstrated that
infections may be a culprit in cognitive impairment as well .
[28]
Similarly, the Oral Infections and Vascular Disease Epidemiology Study (INVEST) demonstrated a direct
[29]
relationship between tooth loss and carotid plaque prevalence Specifically, colonization with pathogenic
periodontal pathogens was associated with carotid artery intima-media thickness (IMT), a measure of
[30]
subclinical vascular disease . INVEST also demonstrated that severe periodontal bone loss was associated
[31]
with a nearly 4-fold increase in risk for the presence of carotid atheroma [odds ratio (OR) 3.64, P < 0.05] .
The study also provided data supporting an effect of the subgingival periodontal bacteria level and both
systolic and diastolic blood pressure in addition to prevalence of hypertension . At a protein level, higher
[32]
secretory phospholipase A2 activity (an inflammatory enzyme associated with atherosclerosis) at high
tertile of etiologic presence presents a mechanistic explanation of the link between periodontal bacteria
[33]
and CVD .

In the Atherosclerosis Risk in Communities (ARIC) study of 8,363 men and women from four United
States communities (aged 52 to 75 years), patients with both high attachment loss and high tooth loss [OR
= 1.5, 95% confidence interval (CI): 1.1 to 2.0] and also edentulous individuals (OR = 1.8, 95%CI: 1.4 to
2.4) had elevated odds of prevalent coronary heart disease (CHD) in comparison with controls with low
attachment loss and low tooth loss. A number of traditional risk factors for CHD were factored in. The
ARIC results thus presented evidence that both tooth loss and periodontal disease (PD) are associated with
[34]
prevalent CHD .
The Periodontitis and Its Relation to Coronary Artery Disease compared 805 patients (< 75 years of age)
with myocardial infarction (MI) and 805 age-, sex- (male 81%), and area-matched controls (mean age 62 ± 8)
without MI. This study determined that periodontitis was more common (43%) in patients than in controls
(33%; P < 0.001). A significant increased risk for MI was observed in periodontitis patients (OR adjusted for
[35]
confounders, 1.28; 95%CI) .

In a Polish case-control study, the level of PD was significantly associated with the risk of acute MI (OR =
2.4, 95%CI: 1.1 to 5.2, P = 0.0203). This was even after an adjustment for age, sex, smoking, hypertension,
[36]
diabetes, body-mass index, education and income . Interestingly, severe infection was sometimes
associated with MI only in females. Similarly in another study, severe periodontitis was more prevalent in
female patients than female controls (14% vs. 4%, P = 0.005). An increased risk for severe periodontitis in
[37]
female patients with a first MI was reported (adjusted OR = 3.72, 95%CI: 1.24 to 11.16, P = 0.005) .