Periodontal treatment improves endothelialdysfunction in patients with severe periodontitisGerald Seinost, MD,a Gernot Wimmer, MD,b Martina Skerget, MD,a Erik Thaller, DDS,b Marianne Brodmann, MD,aRobert Gasser, MD,c Rudolf O. Bratschko, MD,b and Ernst Pilger, MDa Graz, Austria Background Because epidemiological studies provide evidence that periodontal infections are associated with anincreased risk of progression of cardiovascular and cerebrovascular disease, we postulated that endothelial dysfunction, acritical element in the pathogenesis of atherosclerosis, would be present in patients with periodontal disease.
Methods We tested endothelial function in 30 patients with severe periodontitis and 31 control subjects using flow-mediated dilation (FMD) of the brachial artery. The groups were matched for age, sex, and cardiovascular risk factors. Threemonths after periodontal treatment, including both mechanical and pharmacological therapy, endothelial function wasreassessed by brachial artery FMD. Markers of systemic inflammation were measured at baseline and at follow up.
Results Flow-mediated dilation was significantly lower in patients with periodontitis than in control subjects(6.1% F 4.4% vs 8.5% F 3.4%, P = .002). Successful periodontal treatment resulted in a significant improvement in FMD(9.8% F 5.7%; P = .003 compared to baseline) accompanied by a significant decrease in C-reactive protein concentrations(1.1 F 0.9 vs 0.8 F 0.8 at baseline, P = .026). Endothelium-independent nitro-induced vasodilation did not differ betweenthe study groups at baseline or after periodontal therapy.
Conclusion These results indicate that treatment of severe periodontitis reverses endothelial dysfunction. Whetherimproved endothelial function will translate into a beneficial effect on atherogenesis and cardiovascular events needs furtherinvestigation. (Am Heart J 2005;149:1050 - 4.) Periodontal disease is a common chronic infection endothelial function would be impaired in patients with caused by gram-negative bacteria such as Porphyromo- severe periodontitis. We further hypothesized that nas gingivalis, Actinobacillus actinomycetemcomi- periodontal treatment would improve endothelial dys- function, thereby supporting the concept that thera- subgingival severe periodontitis, gingival peutic strategies aimed at reducing cardiovascular risk infection and inflammation destroy the attachment factors translate into improved endothelial health.
apparatus, leading to alveolar bone and tooth loss.
Epidemiological research provides strong evidence that severe periodontitis is a risk factor for cardiovas- cular disease. A number of studies have demonstrated Patients aged 25 to 50 years with severe periodontitis were eligible to participate in the study. Patients were excluded if they had a history of cardiovascular disease, diabetes mellitus, identified relationships between periodontal disease hypertension, or hypercholesterolemia, if they were suffering and cardiovascular disease by no means indicate a from any systemic illnesses or if they had been treated for periodontitis within 6 months of the study. None of them werecurrently taking cardiovascular or antiinflammatory medica-tion, and none of them had been taking antibiotic medication From the aDivision of Angiology, Department of Medicine, University Hospital, Graz, or antioxidant agents within 3 months of the study. In Austria, bDepartment of Prosthetics and Periodontology, School of Dentistry, Graz,Austria, and cDivision of Cardiology, Department of Medicine, University Hospital, addition, healthy volunteers matched for age and sex served as Submitted July 8, 2004; accepted September 23, 2004.
Reprint requests: Gerald Seinost, MD, Division of Angiology, Department of Medicine, University Hospital, Graz, Auenbruggerplatz 15, A-8036 Graz, Austria.
systolic blood pressure z140 mm Hg and/or diastolic blood n 2005, Elsevier Inc. All rights reserved.
pressure V90 mm Hg, according to the American Association/American College of Cardiology All Table I. Participants’ baseline characteristics Table II. Brachial artery parameters and markers for systemicinflammation in control subjects and in patients before and after Values are mean (SD) unless otherwise indicated.
subjects provided written informed consent as approved by yP b .01 versus before treatment.
zP b .05 versus controls.
All clinical parameters were assessed by trained periodontists and a calibration exercise was performed to obtain acceptable the patient’s request. Chlorhexidine gluconate (0.1%) mouth intraexaminer reproducibility. The evaluation included the washes were continued for 14 days. Systemic antimicrobial assessment of bleeding on probing as an indication of an therapy was administered for 7 days and consisted of a existing periodontal inflammation and the measurement of combination of amoxicillin acid and metroni- probing depth and gingival recession on 6 sites on each tooth dazole as adjunctive patients were reevaluated (with the exception of the third molars) using a pressure- 12 weeks after periodontal treatment. In the intervening calibrated digital recording device. Probing depth is defined as period, their compliance was checked twice and a professional the distance from the gingival margin to the base of the cleaning was performed. Residual pockets of more than 5 mm probeable crevice. Gingival recession was measured as the that bled after probing were rescaled. Treatment of periodon- distance from the cementoenamel junction to the gingival titis was considered successful when there was no bleeding on margin. These 2 values were summed for clinical attachment probing and no pocket depth N5 mm at follow-up.
levels, a valid measure of historical periodontalpresence of was Brachial artery reactivity was assessed within 1 week of the involvement of at least 6 teeth with pocket depth N5 mm and initial treatment and 3 months after end of treatment.
loss of attachment of z3 mm in 3 aspects of each involved Endothelium-dependent flow-mediated dilation (FMD) and tooth. In control subjects, periodontal disease was excluded if endothelium-independent nitroglycerin-associated dilation of they had no tooth pocket depth z2 mm and no attachment loss z3 mm. Subjects with intermediate-severity periodontitis were a previously described brief, patients were excluded from the study. Periodontal parameters were studied in a quiet, temperature controlled room in the morning recorded at baseline and 3 months after end of treatment.
after an overnight fast. Two-dimensional images from the rightbrachial artery were obtained above the antecubital crease at baseline and after 1 minute of hyperemia created by 5 minutes’ All underwent conservative nonsurgical periodontal forearm cuff occlusion with an Acuson Sequoia 512 ultrasound consisted of extensive explanation of the system equipped with a 13.0-MHz linear array transducer disease and oral hygiene instruction with several supragingival (Acuson, Mountain View, Calif). After at least 10 minutes of cleaning sessions. After a satisfactory hygiene index had been rest, to allow restoration of baseline conditions, we assessed achieved, all clinical parameters were recorded and a careful endothelium-independent brachial artery dilation by recording subgingival instrumentation was performed. The scaling and 2-dimensional images before and 4 minutes after administra- root planing were carried out according to the individual needs tion of sublingual nitroglycerin. Nitroglycerin was not admin- of the patients, using a variety of hand instruments and, where istered to individuals with clinically significant bradycardia or appropriate, a piezoelectric ultrasonic scaler. The entire hypotension or to individuals with a history of migraine procedure was completed in 2 sessions. Usually, one jaw was headaches. Digitized end-diastolic images were analyzed off- treated per session, starting with the advanced sites. Local line by a single investigator who was blinded to the individuals’ anesthesia was used only occasionally for isolated sites, upon clinical status and image sequence. The lumen-intima bound- Relative flow-mediated (%FMD) and nitroglycerin-associated Markers of systemic inflammation of patients with severe period- (%NAD) dilation of the brachial artery of patients with severe ontitis before and after periodontal treatment and of control subjects.
periodontitis before and after periodontal treatment and of control hs-CRP, high sensitive C-reactive protein.
aries were identified manually with electronic calipers and the The clinical characteristics of 30 otherwise healthy diameter of a vessel segment was determined as an average patients with severe periodontitis and 31 healthy derived from multiple diameter measurements.
controls are summarized in . As shown, the Intima and media thickness (IMT) of the brachial artery was measured at the far wall with electronic calipers above the The structural and functional brachial artery parame- antecubital fossa at the peak of the vessel arch. Measurementswere obtained at 2 sites per image in 2 different images per ters as well as markers of systemic inflammation are patient. The mean of 4 measurements was defined as brachial summarized in Baseline diameter of the brachial artery was comparable between the patient and thecontrol groups and did not change after treatment of periodontitis. Flow-mediated dilation expressed as Concentrations of total cholesterol, triglycerides, high- change in diameter and as percent change was signifi- density lipoprotein, and hemoglobin A1c were measured using cantly lower in patients with periodontitis before treat- automated analyzers (Modular Analytics, Roche/Hitachi, Basel, ment than in healthy controls. Three months after Switzerland; Adams A1c HA-8160, Menarini Diagnostics, treatment, FMD significantly improved and returned to Firenze, Italy). Low-density lipoprotein cholesterol (LDL-C) values comparable to those of healthy controls ).
concentrations were calculated with Friedewald formula.
On regression analysis using age, sex, smoking status, High-sensitivity C-reactive protein was measured with a body mass index, and high-density lipoprotein choles- nephelometric method (Dade-Behring Inc, Deerfield Ill).
terol (HDL-C) as covariates, brachial artery FMD was still significantly impaired in patients with periodontitis( P Group differences in age, blood pressure, lipid profile, b .0001). Nitroglycerin-associated dilation did not erythrocyte sedimentation rate (ESR), high-sensitive C-reactive differ significantly between controls and patients with protein, brachial artery diameter, flow-mediated and nitro- periodontitis before and after treatment ( glycerin-mediated dilation of the brachial artery, and brachial To investigate structural vessel wall alterations, we artery wall thickness were analyzed using unpaired t test.
measured brachial artery IMT. As shown, there was no Analysis of normality was performed with the Kolmogorov- significant difference in brachial artery IMT between Smirnov test. Nonnormally distributed data were logarithmi- cally transformed before comparative analysis. Categorical Patients with periodontitis had significantly higher parameters were analyzed by v2 test or Fisher exact test when baseline levels of ESRs and concentrations of C-reactive required. Univariate analysis of variance with FMD as a protein (than did controls. After periodontal dependent variable and periodontal disease as a fixed factor treatment, C-reactive protein concentrations significant- was used to control for confounders identified by univariate ly decreased and there was a trend toward a reduction in analysis. The paired t test was used to assess changes inbrachial artery diameters and biochemical markers. A P value ESRs (However, differences in white bloodcells did not reach statistical significance in controls and b.05 was considered statistically significant. All analyses werecompleted with SPSS for Windows version 10.1 (SSCP Inc, in patients at baseline and follow-up. There was a trend Chicago, Ill). Data are presented as mean F SD.
toward an inverse correlation between FMD and ESR (r = À0.28, P = .05) and between FMD and C-reactive patients. In the Atherosclerotic Risk in Communities protein concentration (r = À0.24, P = .1) that did not study, the multivariable logistic regression model of cross-sectional data on 6017 persons aged 52 to 75 years There was no statistically significant change in total indicates that severe periodontitis (OR 1.31, CI cholesterol ( P = .28), LDL-C ( P = .37), HDL-C ( P = .71), triglycerides ( P = .06), and systolic ( P = .68) and endothelial dysfunction is an early event in diastolic ( P = .2) blood pressure at follow-up.
atherogenesis before anatomic evidence of atheroscle-rosis appears.
The mechanism by which periodontal disease dis- rupts vascular homeostasis remains unclear. However, The results from this study showed that severe in our study, markers of systemic inflammation were periodontitis generates an inflammatory reaction asso- significantly elevated in patients with periodontitis and ciated with endothelial dysfunction in the conduit decreased after treatment. This finding is consistent brachial artery. These findings are with a with the observation that a variety of therapeutic recently published study by Amar were able strategies to improve endothelial dysfunction are to demonstrate that patients with advanced, but not associated in parallel with a decrease of C-reactive with mild, periodontal disease exhibited endothelial protein levels.A possible pathway of systemic dysfunction and elevated C-reactive protein. A number inflammation in oral infection is the release of exo- of studies have demonstrated associations between the toxins or such as lipopolysaccharides into direct invasion of the vessel wall by oral pathogens ingly, in a recent study, Prasad et able to triggering, in part, an inflammatory response that demonstrate that the serologic response to multiple translates into endothelial dysfunction. Indeed, topical intracellular pathogens (cytomegalovirus, herpes sim- oral inoculation with the major periodontal pathogen plex virus 1, hepatitis A virus, and bacteria such as P gingivalis has recently been demonstrated to Chlamydia pneumoniae and Helicobacter pylori) was an independent risk factor for the endothelial dysfunc- tion and the presence and severity of coronary artery have demonstrated that periodontal pathogens exist in disease. The results from their study support the atherosclerotic lesions actively invade human and concept that cardiovascular risk is related to the aggregate number of potentially atherogenic pathogens A potential limitation to our study is that the association between severe periodontitis and endothelial Endothelial dysfunction significantly improved after dysfunction may reflect residual confounding by known successful periodontal treatment and returned to values or yet unknown cardiovascular risk factors despite our comparable to those of the healthy control group. Thus, attempt to match the groups and check for confounding our results indicate that there is a causal relationship with regression analysis. Whether the effect on endo- between periodontal disease and endothelial dysfunc- thelial function and C-reactive protein actually was due tion. The influence of infectious agents, especially C to mechanical or pharmacological periodontal treatment pneumoniae, as contributors to atherogenic remains unclear. It is, however, unlikely that an unspecific antiinflammatory effect of antibiotic therapy randomized, prospective, controlled trial, Parchure et was responsible for improved endothelial function and were able to show that azithromycin treatment for 5 inflammatory markers 12 weeks after the end of weeks produced significant improvement in FMD in patients with coronary artery disease and serologic Regardless of the mechanisms, we have shown that evidence of C pneumoniae infection. Another severe periodontitis is associated with significant gation has failed to demonstrate an association endothelial dysfunction that is reversible after success- treatment of C pneumoniae and endothelial ful periodontal treatment. There is increasing evidence a disparity that may be caused by the short-term from numerous clinical trials that improvement of antibiotic treatment regimens used in that study. How- ever, there is a lack of direct proof that therapeutic cardiovascular is therefore reasonable to improvement in endothelial function due to reduction of conduct further research to determine whether pathogen burden translates into lower cardiovascular improved endothelial health after successful periodon- tal treatment in high-risk patients prevents atheroscle- We demonstrated functional brachial artery impair- rotic complications. In the meanwhile, patients should ment in patients with periodontal disease in the absence be made aware of the possible relationship between of structural vessel wall alterations in relatively young periodontal disease and cardiovascular events.
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