Effect of Intensive Periodontal Therapy on Vascular Function

In the last decade considerable evidence has supported the hypothesis that chronic low-grade infections, periodontitis included, and the inflammatory responses associated with them may play a significant role in the onset of atherosclerosis. An inflammatory alteration of the normal endothelial activity is thought to be one of the mechanisms that may link infection with atherosclerosis. It consists of loss of the normal vasodilation, antiplatelet and antithrombotic properties of the vascular walls and it is frequently called endothelial dysfunction. Impaired endothelium-dependent dilatation, an early functional marker of endothelial dysfunction has been demonstrated in young populations with family history of cardiovascular diseases. In the past 15 years a new non invasive and reproducible technique called Flow mediated dilatation (FMD) has been used to assess endothelial function.

Periodontitis is a chronic infection of the tooth supporting apparatus caused primarily by anaerobic gram negative bacteria organised in a biofilm (commonly known as sub-gingival dental plaque); it leads to inflammatory destruction of the periodontal ligament and alveolar bone and eventually to tooth exfoliation. Periodontitis is highly prevalent in both industrialised and developing countries with 10-15% of the adult population being affected by severe forms of this disease. Recognized risk factors include genetic polymorphisms in inflammatory genes, environmental exposures such as cigarette smoking, and systemic diseases such as diabetes. Local periodontal production of prostaglandins and pro-inflammatory cytokines has been associated with activation of matrix metalloproteinases and eventually to destruction of the periodontal ligament and alveolar bone. It is the primary cause of tooth loss in adult populations and as such leads to long term disability and increased treatment needs.

Local periodontal infections have been associated with a systemic response characterized by increased serum levels of C-reactive protein (CRP), hyper-fibrinogenemia, moderate leukocytosis, as well as increased serum levels of IL-1 and IL-6 when compared with unaffected control populations.

Several epidemiological studies have associated increased levels of acute phase markers with higher risk for cardiovascular atherosclerotic events. Among these markers, C-reactive protein is considered to be one of the most sensitive and probably to be an independent risk factor of atherosclerosis. It is produced by the liver presumably for adaptive or defensive reasons in response to a variety of inflammatory stimuli, including chronic low grade infections.

In a recently completed pilot trial we have been able to establish that treatment of periodontal infections resulted in a significant decrease in serum CRP. In that study, treatment of periodontal infections led to a significant decrease in serum CRP (0.5 mg/L, 95% CI 0.4 to 0.7 mg/L) and IL6 in otherwise healthy individuals affected with severe, generalized periodontitis and indicated that periodontitis contributed to the systemic inflammatory responses.

The treatment associated decrease in systemic inflammatory markers observed in this study supports the hypothesis that periodontal infections, along with chronic low grade infections in other body districts, contribute to the inflammatory burden of an individual and may play a contributory etiologic role in atherosclerosis. It remains to be established whether or not the observed improvements in serum CRP have an impact on functional vascular parameters and endothelial function/dysfunction.

The relationship between periodontal treatment and changes in serum CRP is likely to be bimodal: an increase associated with the delivery of the standard subgingival instrumentation and the associated bacteremia and tissue damage is expected shortly after treatment is delivered.

Preliminary trials from our group aimed at the establishment of the pattern of CRP changes in the first days following delivery of periodontal therapy. The data indicate that serum CRP levels sharply increase after treatment but that values tend to return to baseline levels by one week. This bimodal pattern of changes in serum CRP levels is important since previous investigations have established links between functional vascular parameters such as flow mediated dilatation (FMD) and serum markers of systemic inflammation such as CRP.

Periodontal therapy therefore may lead to an initial improve FMD parameters in subject were periodontitis contributes to systemic inflammation and atherosclerosis. The hypothesis of the existence of a causal association between the systemic infectious/inflammatory burden represented by periodontitis and endothelial function assessed by FMD is the subject of the proposed investigation.

Compare the effects of an intensive periodontal treatment regimen with a community based periodontal care approach in terms of changes in:

• Flow mediated dilatation of the brachial artery (primary outcome)
• Acute phase response in serum (CRP, IL-6,fibrinogen)
• Clinical periodontal parameters: PI, BoP, PPD (CAL)
• Presence of periodontal pathogens in the periodontal pockets before and after treatment
• Patient perception and adverse events associated with the treatment experience This will be a randomized controlled clinical trial. Its design will be parallel arm, single blind; outcomes will be evaluated over a 6 months period and will include approximately 120 subjects. Two interventions will be compared: test treatment will be an intensive regimen of periodontal therapy consisting of oral hygiene instructions and subgingival debridement delivered at two appointments over a 24 hour period; control treatment will consist of a community based periodontal care approach consisting of supragingival removal of deposits delivered at two appointments over a 24 hour period. The control group will receive the intensive regimen upon completion of the study or upon evidence that periodontitis is progressing. Subjects with moderate to severe periodontitis will be recruited among those referred for care to the Periodontal Clinic of the Eastman Dental Hospital. The primary outcome measure of this study will be changes in Flow Mediated Dilatation (FMD) of the brachial artery. Secondary outcomes will include changes in serum CRP and plasma fibrinogen. Periodontal, microbiological and subjective outcomes will be evaluated as control outcomes. The primary and the secondary outcome variables will be evaluated before treatment and at 1 day, 7 days, 2 months and 6 months following completion of treatment. Subjects will be randomized to treatment stratifying for smoking status by a study registrar. Treatment allocation will be concealed to study personnel by using opaque envelopes and to the examiner by making treatment records unavailable. All laboratory and FMD analyses will be performed by unrelated study personnel blind with respect to treatment allocation or stage of progression of the trial. Intent to treat analyses will be performed by a statistician blind with respect to treatment allocation.