INTRODUCTION: For over a decade, it has been hypothesized that microbial agents are responsible for the development of atherosclerotic disease. Prevalent periodontal pathogens including Aggregatibacter actinomycetemcomitans, Tannerella forsythia, Porphyromonas gingivalis, and Prevotella intermedia have all been identified in atheromatous plaques. In addition, a group of epidemiological studies, as well as preliminary animal studies have suggested an association between endodontic disease, systemic inflammation, and cardiovascular disease. The purpose of the present series of studies is to clarify the association between chronic endodontic infections and the systemic immune response to the microbes causing these lesions through an investigation with the following aims: 1. Determine if atheromatous plaques are larger in atherosclerosis susceptible mice with periapical lesions than those without periapical lesions 2. Determine if periapical lesion size in atherosclerosis susceptible mice correlates with the degree of atheromatous plaque formation 3. Systematically review the literature to determine if the levels of systemic inflammatory markers are altered in humans with apical periodontitis compared to those systemic marker levels in humans with healthy periapical status and 4. Determine if systemic antibody levels 8 prevalent microorganisms from chronic primary endodontic infections, are higher in patients with atherosclerosis undergoing endarterectomy compared with those same systemic antibody levels in healthy control patients. METHODS: For aim #1 and aim #2 eight atherosclerosis susceptible female mice (N=8) were obtained and randomly placed into two separate groups of four as follows: 1. with pulp exposure and endodontic inoculation (N=4) - "EI" 2. without pulp exposure (N=4) - "w/o pulp exposure". The mice were euthanized, their aortic arches were dissected for atheroma size measurement, and their mandibles were processed for periapical lesion area measurement. For aim #3 a comprehensive literature search with no language restriction was undertaken to identify all studies that reported on the relationship between AP and circulating or systemic levels of inflammatory markers between 1948 and 2012. Studies with similar outcome variables were grouped and a meta-analysis was performed to evaluate the most prevalent markers. For aim #4, two groups of patients were selected from a cohort at the Veterans Administration Hospital, Baltimore, MD. The experimental group consisted of ten patients with a clinical diagnosis of carotid stenosis who had undergone recent endarterectomy procedures (n=10), and the control group consisted of 14 patients with a diagnosis of varicose veins (n=14). Each patient underwent comprehensive oral examination, and a blood sample was taken for each patient. Bacterial phenotypes associated with primary endodontic infections were used for immuno-checkerboard analysis to identify differences in IgG antibody levels between the groups. RESULTS: Atheromatous plaque sizes were different among the groups, and difference was borderline significant (p =0.06). There was a statistically significant correlation between lesion size and atheroma size among the groups (p=0.001). Apical periodontitis in humans was associated with increased levels of CRP, IL-1, IL-2, IL-6, ADMA, IgA, IgG, and IgM (p < 0.05) as compared to the levels of these markers in humans without apical periodontitis. Antibody levels to F. nucleatum and P. micra were not significantly different among the two groups (p > 0.05). CONCLUSIONS: 1. Exposure to endodontic pathogens leads to the development of periapical lesion area that was associated with larger atheroma formation in an animal model. 2. There was a significant correlation between periapical lesion area and atheroma size in this model. 3. In patients, apical periodontitis showed an association with increased levels of CRP, IL-1, IL-2, IL-6, ADMA, IgA, IgG, and IgM 4. Systemic antibody levels to F. nucleatum and P. micra were not increased in CEA patients compared with healthy controls.