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Full-mouth Tooth Extraction Lowers Systemic Inflammatory and Thrombotic Markers of Cardiovascular Risk
1 Sydney Dental Hospital, 2 Chalmers Street, Surry Hills NSW 2010, Australia; Correspondence: * corresponding author, barbara.taylor{at}email.cs.nsw.gov.au
Prior studies of a link between periodontal and cardiovascular disease have been limited by being predominantly observational. We used a treatment intervention model to study the relationship between periodontitis and systemic inflammatory and thrombotic cardiovascular indicators of risk. We studied 67 adults with advanced periodontitis requiring full-mouth tooth extraction. Blood samples were obtained: (1) at initial presentation, immediately prior to treatment of presenting symptoms; (2) one to two weeks later, before all teeth were removed; and (3) 12 weeks after full-mouth tooth extraction. After full-mouth tooth extraction, there was a significant decrease in C-reactive protein, plasminogen activator inhibitor-1 and fibrinogen, and white cell and platelet counts. This study shows that elimination of advanced periodontitis by full-mouth tooth extraction reduces systemic inflammatory and thrombotic markers of cardiovascular risk. Analysis of the data supports the hypothesis that treatment of periodontal disease may lower cardiovascular risk, and provides a rationale for further randomized studies.
Key Words: periodontal disease • cardiovascular disease
Periodontal disease, the most common chronic infection in humans, is caused by pathogenic bacteria that colonize as oral biofilms. Periodontitis, its severe form, affects approximately 15–20% of dentate adults in Australia (Barnard, 1993) and induces chronic inflammation and immune reactions that result in the loss of the bone and soft tissues that support the teeth in the jaws. Observational studies show that periodontitis is associated with an increased risk of myocardial infarction and stroke, although a causal link has not yet been proven (Scannapieco et al., 2003). The effect may be due to the direct action of periodontal pathogens or their products on endothelial cells via transient bacteremia (Geerts et al., 2002) or indirectly via products of the inflammatory response (Choi et al., 2002), since inflammation is currently considered to play a central role in the pathogenesis of cardiovascular disease (CVD) (Ridker et al., 2004). While several case-control and cohort studies have indicated an association between periodontitis and CVD (Mattila et al., 1989; DeStefano et al., 1993; Beck et al., 1996), not all studies have found a significant association (Hujoel et al., 2000; Mattila et al., 2000; Howell et al., 2001). A limitation of observational studies is that traditional risk factors, such as age, cigarette smoking, and diabetes, are common to both periodontitis and CVD. Furthermore, both conditions are influenced by factors such as level of education, income, psychosocial stress, and social isolation (Hujoel et al., 2000). Thus, although significant associations persist after adjustment for known confounders, there remains the possibility that they primarily show that people who are more health-conscious and have better access to health care are at lower risk of both CVD and periodontitis. Establishing whether or not there is a causal link between periodontitis and CVD is important for several reasons. First, it fits with current thinking about atherosclerosis as an inflammatory disorder. Second, it would suggest that cardiovascular risk assessment should include a periodontal evaluation. Third, demonstration of causality would suggest that prevention and treatment of periodontitis could reduce CVD. The purpose of this study was to investigate whether elimination of periodontitis by full-mouth tooth extraction (FME) reduces levels of known hemostatic indicators of risk.
Study Group The target population for the study was adults over 40 yrs of age who presented to the Sydney Dental Hospital with advanced periodontitis. Each patient had at least 2 teeth with periodontal pockets of  6 mm in conjunction with attachment loss and bleeding on probing. The patients were examined by hospital clinicians independent of the study. If FME was the recommended treatment, and there were no general health complaints or symptoms consistent with active systemic inflammation or infection, the patients were invited to participate in the study.
Study Design At the initial visit, 27 of the patients presented with loose teeth, 17 presented with pain triggered by chewing with loose teeth or by lacerating the tongue, lips, or opposing ridge with the sharp edges of teeth, six patients presented with the request for extraction of all of their remaining teeth, and 17 presented with various other symptoms. Fifty-two persons had one or more extractions on the day of the initial visit, and one patient with a dry socket received a seven-day course of amoxycillin. The medical history of the participants was recorded. The history focused on cardiovascular risk factors, including diabetes mellitus, hypertension, hyperlipidemia, smoking, and any history of cardiac, cerebral, or peripheral vascular disease. The medical examination included the patients’ height, weight, temperature, blood pressure, heart rate, and ECG recording. The dental examination included charting of probing pocket depth and recession at 6 sites around each tooth. The sums and averages of probing pocket depths and recession were calculated for each participant. Most extractions (42) were completed within 1 to 4 wks of initial presentation. Another 15 persons had all their teeth extracted between 4 and 8 wks after presentation, and a further ten persons took more than 8 wks to complete extractions. All participants completed FME within 14 wks. Approximately 3 mos after FME, the medical history was repeated and a medical examination performed. An oral examination was conducted at the same time, mainly to confirm the absence of teeth, tooth fragments, or oral ulceration. The study was approved by the Ethics Review Committee of the Sydney Dental Hospital, and written informed consent was obtained from all study participants.
Blood Sampling and Hemostatic Analyses
Statistical Evaluation
Seventy-seven persons were initially enrolled, and 67 completed the study. Three persons withdrew consent because they decided not to proceed with treatment. One had FME at T1, and another was found to have disseminated cancer. Four persons dropped out after the T2 visit, and one dropped out after the T1 visit.
The characteristics of the 67 persons who completed the study are shown in Table 1
The mean levels of risk indicators before and after periodontal treatment are shown in Table 2  . There were no significant differences between levels of the markers at T1 and T2. CRP levels fell significantly from T1 to T3 and from T2 to T3. PAI-1 levels fell significantly from T1 to T3. Values for TPA and fibrinogen also showed a downward trend from T1 to T3, although this was not significant. Fibrinogen values decreased significantly from T2 to T3.
Total white blood cell count, neutrophils, lymphocytes, and platelets displayed a significant reduction after tooth extraction (Table 3 ). Hemoglobin levels and red blood cell counts showed significant increases after FME (Table 3). By contrast, glycosylated hemoglobin, urea, electrolytes, glucose, and cholesterol measurement did not change significantly during the observation period (data not shown).
Prevalence and severity of periodontitis are higher in smokers than in non-smokers (Kerdvongbundit and Wikesjö, 2002). The data were therefore analyzed according to smoking status. Non-smokers were defined as persons who had never smoked or who had given up smoking prior to the study, while smokers were those who smoked during the study. None of the study participants changed his/her smoking habits during the course of the study. Similar downward trends in inflammatory and hemostatic markers were seen for both non-smokers and smokers. Variables that showed significant differences from T1 to T3 are displayed in Table 4 . The magnitudes of change were greater among the non-smokers, and significant reductions were seen in CRP, white blood cells, neutrophils, lymphocytes, and platelets after FME in the non-smoking group only.
Associations at the outset of the study—between sums and averages of probing pocket depths and recession, and between inflammatory and cardiovascular risk indicators—were examined. No statistically significant correlations were found between clinical variables (number of teeth, age, and sum of PPD) and laboratory measurements (Spearman correlation coefficients, p > 0.05), with the exception of mean periodontal pocket depth, which was found to be inversely associated with hematocrit values (rs = –0.342, p < 0.05).
The present study shows that blood levels of CRP, PAI-1, and fibrinogen, established indicators of risk for CVD, are reduced in patients with severe periodontitis after extraction of all teeth. Even though the number of teeth was limited prior to FME (Table 1  ), and therefore the infected periodontal surface area was not particularly large, FME resulted in a significant reduction in several of the parameters examined. An important recent advance in the understanding of the pathogenesis of CVD has been recognition of the role of inflammation and thrombosis in atherosclerosis and acute coronary syndromes (Ridker et al., 2004). Inflammatory cells have been shown to play an important role in the thinning and weakening of the cap overlying atherosclerotic plaques. Whether thrombosis occurs following plaque disruption depends on a complex balance of factors, including PAI-1, TPA, and fibrinogen. PAI-1, the major antifibrinolytic, and TPA are mainly produced in endothelium and platelets. TPA forms inactive complexes with PAI-1 in the blood and tissues. Higher levels of TPA antigen therefore reflect impaired fibrinolytic potential. Increased levels of fibrinogen result in its binding to platelets, causing platelet aggregation and promotion of fibrin formation, thus contributing to plasma viscosity. Epidemiological studies have shown that increased levels of CRP, fibrinogen, and PAI-1 are strong predictors of CVD (Hamsten et al., 1987; Jadhav and Tofler, 1996). Hepatic production of CRP, a strong acute-phase protein, is induced by pro-inflammatory cytokines in response to tissue injury and infection, both of which occur in periodontitis (Loos et al., 2000). Chronic infections are known to be associated with the development of CVD. Microbes can directly damage the endothelium, as has been shown for cytomegalovirus and Helicobacter pylori (Grau et al., 1995; Libby et al., 1997). Periodontal pathogens have been found in atheromas from patients with severe periodontitis, and periodontopathogenic bacteria such as Porphyromonas gingivalis can adhere to and invade endothelial cells (Li et al., 2000). Microbial infection may induce the release of pro-inflammatory cytokines that increase levels of CRP, fibrinogen, and PAI-1, the same molecules that are recognized indicators of risk for CVD. Cross-sectional studies have demonstrated that plasma levels of inflammatory markers such as CRP, fibrinogen, von Willebrand factor, interleukin-6, and leukocyte counts are increased in patients with periodontal disease, in comparison with periodontally healthy patients (Shklair et al., 1968; Fey and Fuller, 1987; Tatakis, 1992; Kweider et al., 1993; Ebersole et al., 1997; Loos et al., 2000; Slade et al., 2000). In less severe periodontitis, reduction in levels of interleukin-1 and CRP have also been reported after periodontal treatment (D’Aiuto et al., 2004). This indicates that the inflammatory response to periodontitis contributes to the whole-body inflammatory burden. It has been shown that persons with chronic periodontitis display signs of a subclinical systemic inflammatory condition (Ebersole et al., 1997). The results of the present study support this notion: Counts of white cells, neutrophils, and lymphocytes, which are systemic markers of inflammation, were reduced after FME in the current patients. Platelets have their main function in hemostasis, but they also play a role in inflammatory processes, and their numbers increase in chronic inflammation (Klinger and Jelkmann, 2002). In this study, the number of platelets decreased after treatment. In sum, the present results show that the presence of untreated periodontitis has systemic inflammatory effects. Periodontitis has been reported to be associated with signs of "anemia of chronic disease", as expressed by lower hematocrit, lower numbers of erythrocytes, and lower hemoglobin levels (Hutter et al., 2001). The presently detected inverse correlation between hematocrit and mean periodontal pocket depth suggests that this too is related to periodontitis severity. We furthermore found a significant increase in hemoglobin after treatment, indicating that the mildly anemic condition in periodontal patients is likely to be due to the presence of periodontitis. Smoking is a major confounding factor for studies of cardiovascular and periodontal diseases, both of which have been shown to be associated with increased CRP levels and increased white blood cell counts (Kweider et al., 1993; Fredriksson et al., 1999). We analyzed our data according to smoking status. Downward trends in inflammatory and cardiovascular risk indicators were observed in both smoking and non-smoking groups, but they were more pronounced in the non-smoking group, where several significant differences before and after treatment were found. By contrast, the differences were smaller and lost statistical significance in the smoking group (with the exception of the platelet count, which increased). In summary, treatment of advanced periodontitis by FME reduced systemic levels of hemostatic indicators of cardiovascular risk and inflammatory mediators. This means that induction of a systemic inflammatory and prothrombotic state may be a mechanism by which chronic periodontitis increases the risk of myocardial infarction and stroke. The findings suggest that treatment of periodontitis may reduce the risk of cardiovascular disease. FME is a severe treatment and not suitable for most patients. Future studies will have to determine if other oral interventions, such as more limited periodontal treatment for less severe disease, can also reduce systemic levels of the inflammatory and thrombotic risk factors.
This study was supported by the Sydney Dental Hospital, the Royal North Shore Hospital, and the University of Oslo. The authors thank the staff and patients of the Sydney Dental Hospital for their assistance. Received for publication February 8, 2005. Revision received May 5, 2005. Accepted for publication August 5, 2005.
Journal of Dental Research, Vol. 85, No. 1,
74-78 (2006) This article has been cited by other articles:
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