Impact of Gum Infection on Heart Disease

Epidemiological studies indicate that individuals with severe periodontal disease have
significantly increased risk for cardiovascular disease. Periodontal disease, a chronic
bacterial infection of the gums, is associated with recurrent bacteremia and a state of
systemic inflammation that may convert endothelial cells to a pro-atherogenic phenotype with
increased expression of inflammatory factors and loss of the anti-thrombotic, growth
inhibitory, and vasodilator properties of the endothelium, including a decrease in the
biological activity of nitric oxide. In human subjects, endothelial dysfunction has evolved
into a well-accepted indicator of early atherosclerosis and predictor of increased
cardiovascular disease risk. We have recently demonstrated a strong association between
severe periodontal disease and endothelial vasomotor dysfunction in a case control study of
otherwise healthy human subjects. In that study, periodontal disease was also associated
with higher plasma levels of the acute phase reactant C-reactive protein (CRP). These
results support the hypothesis that severe periodontal disease induces a state of systemic
inflammation that impairs endothelial function, however, the cross-sectional design leaves
open the possibility that confounding factors explain the results. We now propose to
determine whether effective treatment of periodontal disease improves endothelial function
(Aim 1) and reduces inflammation (Aim 2) in a randomized intervention study. Patients will
receive comprehensive periodontal treatment designed to produce a state of periodontal
health (scaling and root planing and periodontal surgery with re-treatment as needed) or
routine oral hygiene and will be followed for 24 weeks. The study will examine
endothelium-dependent brachial artery flow-mediated dilation, systemic markers of
inflammation and endothelial activation (CRP, IL-6, myeloperoxidase, and ICAM-1), and oral
markers of periodontitis (PGE2, myeloperoxidase, and pathogen DNA) before and after
treatment. Compared to oral hygiene (which will stabilize, but not reverse periodontal
disease), we hypothesize that comprehensive treatment of periodontal disease will improve
endothelium-dependent dilation and reduce local and systemic inflammation. Further, we
suggest that the degree of improvement in endothelial function will relate to the degree of
reduction in specific markers of inflammation. Such results would provide much stronger
evidence for causal links between periodontal disease, systemic inflammation, and
endothelial dysfunction, a recognized surrogate for cardiovascular risk. The proposed
studies will provide new insights into how periodontal disease contributes to cardiovascular
disease risk in human subjects and may lead to new approaches to therapy.

Inclusion Criteria:

1. The study seeks to enroll patients with periodontal disease and no other major
co-morbidities including cardiovascular disease or other major medical problems.

2. In this intervention study, cigarette smokers will be permitted as justified below
and randomized in stratified fashion to ensure equal numbers in the two treatment
groups.

Exclusion Criteria:

1. Known cardiovascular disease including coronary heart disease, cerebral vascular
disease, peripheral vascular disease, valvular heart disease, and congestive heart
failure.

2. Major coronary risk factors including diabetes mellitus, hypertension,
hypercholesterolemia requiring treatment according to the ATP-III guidelines.

3. Other major illness including cancer, liver disease, renal disease, pulmonary
disease, chronic infectious disease (including HIV and hepatitis C infection),
rheumatological disease, hematological disease, or any condition requiring
hospitalization or chronic medical therapy.

4. Use of antibiotics within three months.

5. Use of oral contraceptives or hormone replacement therapy.

6. Major psychiatric illness requiring treatment or that might interfere with the
ability to understand and cooperate with the protocol.

7. Ongoing drug or alcohol abuse.

8. Use of sildenafil (Viagra) within 7 days because of the risk of marked hypotension
with nitroglycerin administration.

9. History of migraine headaches that might be exacerbated by nitroglycerin.

10. Use of cholesterol lowering therapy, angiotensin converting enzyme inhibitors
(subjects should not be taking these drugs because they will have no history of
cardiovascular disease risk factors).

11. Antioxidant vitamins (vitamin C or vitamin E) in doses exceeding the Recommended
Dietary Allowances (RDA), (60 mg/day and 30 IU/day, respectively).

12. Pregnancy, as diagnosed by serum beta-hCG.