Volume 80 • Number 5

Periodontal Therapy Reduces Plasma

Levels of Interleukin-6, C-Reactive
Protein, and Fibrinogen in Patients With
Severe Periodontitis and Refractory
Arterial Hypertension
Fábio Vidal,* Carlos Marcelo S. Figueredo,* Ivan Cordovil,† and Ricardo G. Fischer*

Background: Recent epidemiologic studies suggest that

inflammation is the link between periodontal diseases and car-
diovascular complications. This study aimed to evaluate the
effects of non-surgical periodontal treatment on plasma levels
of inflammatory markers (interleukin [IL]-6, C-reactive protein
[CRP], and fibrinogen) in patients with severe periodontitis and
refractory arterial hypertension.

C
ardiovascular disease (CVD) is
Methods: Twenty-two patients were examined and ran- the leading cause of death in
domly divided into two groups. The test group was composed Western industrialized countries.1
of 11 patients (mean age, 48.9 – 3.9 years) who received peri- Classic modifiable risk factors, such as
odontal treatment, whereas the control group had 11 patients smoking, diabetes, hyperlipidemia, and
(mean age, 49.7 – 6.0 years) whose treatment was delayed for arterial hypertension, are present in 50%
3 months. Demographic and clinical periodontal data were of the patients with CVD, and the treat-
collected, and blood tests were performed to measure the ment of these conditions may reduce
levels of IL-6, CRP, and fibrinogen at baseline and 3 months morbidity and mortality.2 Hypertension
later. is the product of a dynamic interaction
Results: The clinical results showed that the mean percent- between diverse genetic, physiologic,
ages of sites with bleeding on probing, probing depth (PD) 4 to environmental, and psychosocial fac-
5 mm, PD ‡6 mm, clinical attachment loss (CAL) 4 to 5 mm, tors.3 Patients whose blood pressure
and CAL ‡6 mm were significantly reduced in the test group 3 remains persistently high despite the
months after periodontal treatment. There were no significant appropriate use of at least three classes
differences between the data at baseline and 3 months in the of antihypertensive drugs, including a
control group. Periodontal treatment significantly reduced the diuretic, are diagnosed as having refrac-
blood levels of fibrinogen, CRP, and IL-6 in the test group. tory hypertension.4 Inflammation may be
Conclusion: Non-surgical periodontal therapy was effective involved in the initiation and develop-
in improving periodontal clinical data and in reducing the ment of hypertension by the action of
plasma levels of IL-6, CRP, and fibrinogen in hypertensive pa- proinflammatory mediators.5 Inflamma-
tients with severe periodontitis. J Periodontol 2009;80:786- tion was associated with endothelial
791. dysfunction6 and increased arterial stiff-
ness.7 Arterial stiffness is an indepen-
KEY WORDS
dent predictor of mortality in patients
Albumins; C-reactive protein; cardiovascular disease; with hypertension,8 and the reduction of
fibrinogen; periodontitis. arterial stiffness should be a goal in the
treatment of hypertension.9
Some systemic inflammatory markers
* Department of Periodontology, Faculty of Odontology, Rio de Janeiro State University,
Rio de Janeiro, RJ, Brazil. may indicate the severity of inflammation,
† Department of Hypertension, National Institute of Cardiology, Rio de Janeiro, RJ, Brazil. and their levels have been associated
with CVDs, including hypertension.10-12

doi: 10.1902/jop.2009.080471

786
J Periodontol • May 2009
Fibrinogen and C-reactive protein (CRP), products of
the acute-phase reaction, were demonstrated to be in-
dependent cardiovascular risk factors for CVDs.13,14
Elevated CRP has been associated with an increased
risk for CVDs, atherosclerosis, and the presence
and development of hypertension.15,16 Moreover,
elevated CRP levels are associated with artery endo-
thelial dysfunction17 and arterial stiffness.18,19 Peri-
odontal treatment improved endothelial dysfunction
in recent studies.20,21 Kim et al.19 suggested that CRP
could be a useful marker of arterial stiffness in treated
hypertensive patients and a possible target for arterial
inflammation in hypertension. Fibrinogen was recog-
nized as an independent coronary heart disease risk
factor and an inflammatory marker.22 Together with
CRP, fibrinogen was considered predictive for future
cardiovascular risk.23 Interleukin (IL)-6 is a major ini-
tiator of the acute-phase response by hepatocytes, a
primary determinant of CRP production,24,25 and is
associated with incident acute coronary events.26
IL-6 is the major initiator of the acute-phase response
by hepatocytes and a primary determinant of hepatic
CRP production. IL-6 is associated with incident acute
coronary events26 and hypertension risk.16 Periodon-
tal therapy reduced the plasma levels of IL-6 and im-
proved endothelial function.20
Periodontitis is a chronic low-grade inflammatory
disease of the tooth-supporting tissues that may lead
to tooth loss27 and may increase blood levels of in-
flammatory markers, including IL-6, CRP, and fibrin-
ogen.28-31 However, there are controversial data
about the effects of periodontal treatment on inflam-
matory markers.29,31,32
Therefore, the aim of the present study was to eval-
uate the effects of non-surgical periodontal therapy on
serum levels of plasma inflammatory markers (IL-6,
CRP, and fibrinogen) in patients with severe periodon-
titis and refractory arterial hypertension.
MATERIALS AND METHODS
Twenty-two patients with severe primary non-respon-
sive (refractory) arterial hypertension, enrolled for treat-
ment at the Hypertension Department, National Institute
of Cardiology, were selected for the study from June to
December 2007. Refractory hypertension is diagnosed
when blood pressure levels remain >140/90 mm Hg
while a patient is engaged in a treatment program and
uses three or more classes of antihypertensive drugs,
including a diuretic.4 The patients were under the super-
vision of a cardiologist and were medicated with beta-
blockers, angiotensin-converting enzyme inhibitors,
and a diuretic. The patients were treated in the cardiol-
ogy department for 5 to 8 years. Periodontal examina-
tion included plaque index (PI);33 bleeding on probing
(BOP), recorded as present or absent; probing depth
(PD); and clinical attachment level (CAL). PD and
Vidal, Figueredo, Cordovil, Fischer
CAL were evaluated on six sites/tooth (mesio-buccal,
buccal, disto-buccal, mesio-lingual, lingual, and
disto-lingual), whereas PI and BOP were evaluated
on four sites/tooth (mesial, buccal, distal, and lingual).
The examination was performed by the same cali-
brated operator (kappa = 0.91) using a controlled-
pressure periodontal probe (20 to 25 g/F).‡
The inclusion criteria were ‡12 teeth, at least four
sites with PD ‡4 mm and five sites with CAL ‡6 mm,
and compliance with treatment for hypertension.
The exclusion criteria included pregnancy, previous
periodontal therapy, systemic conditions that contra-
indicated periodontal therapy or that might affect the
progression or treatment of periodontitis (e.g., diabe-
tes mellitus or history of infective endocarditis), and
the use of medications (e.g., antibiotics or anti-inflam-
matory drugs). Patients were consecutively recruited
and randomly assigned, by means of a draw, to the
test or control group.
The test group was composed of 11 patients (five
men and six women; age range, 43 to 56 years; mean
age, 48.9 – 3.9 years), whereas the control group had
11 patients (six men and five women; age range, 39
to 62 years; mean age, 49.7 – 6.0 years). There were
two smokers (>10 cigarettes per day) in each group.
On the morning of the periodontal appointment, blood
samples were collected and immediately processed,
masked by the laboratory staff from the hospital at the
National Institute of Cardiology, Rio de Janeiro, RJ,
Brazil, to quantify the plasma levels of IL-6, CRP,§ and
fibrinogen.i Patients from the test group received non-
surgical periodontal therapy, whereas patients in the
control group had their treatment delayed for 3 months.
Periodontal therapy included oral hygiene instructions
and supra- and subgingival scaling, which were per-
formed using a sonic instrument¶ and Gracey curets#
and followed the American Academy of Periodontol-
ogy recommendations.34 There was no limit to the ap-
pointments; however, in general, patients were seen
four to six times over 2 weeks. The control group
was recalled 3 months after the baseline visit; the test
group was recalled 3 months after the last appointment
for periodontal therapy, for reassessment of the peri-
odontal parameters, and to repeat the blood test.
The study respected the principles of the Declara-
tion of Helsinki, was revised and approved by the Hos-
pital’s Ethical Board, and all patients gave their
written consent to participate in the study.
Statistical Methods
A post hoc calculation showed that with a sample size
of nine patients in each group, there was 80% power to
‡ Hawe ‘‘Click-probe,’’ Hawe Neos Dental, Zurich, Switzerland.
§ Dade Behring, Amsterdam, The Netherlands.
i Sigma, St. Louis, MO.
¶ Sonic Borden, Kavo, Joinville, SC, Brazil.
# Hu-Friedy, Chicago, IL.
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Periodontal Therapy in Refractory Arterial Hypertension Volume 80 • Number 5

detect, at a 0.05 level, a 50% reduction in the mean
percentage of sites with PD and CAL ‡6 mm. The t test
was used for normally distributed data, whereas the
Mann-Whitney test was used to compare non-nor-
mally distributed data at baseline. The x2 test was
used to compare categoric data at baseline. To verify
differences between clinical and laboratory values at
baseline and 3 months after periodontal therapy,
the paired t test and the Wilcoxon rank test were used
to compare normally and non-normally distributed
data, respectively. All statistical analyses were carried
out with a statistical program,** with a significance
level of 5% (P <0.05).
3 months after periodontal treatment. There was no
difference in the mean percentage of sites with dental
plaque (Table 2).
There was no difference between the groups at
baseline for any of the laboratory parameters studied.
In the test group, there was a significant reduction in
the levels of IL-6 (P = 0.03), fibrinogen (P = 0.03),
and CRP (P = 0.005) 3 months after periodontal ther-
apy. In the control group, the levels of IL-6 (P = 0.01)
and CRP (P = 0.01) had increased significantly after
3 months without periodontal therapy. No significant
differences were observed with regard to fibrinogen
(P = 0.75) levels in the control group (Table 3).

RESULTS DISCUSSION
There were no significant differences between the test Our results showed that periodontal therapy signifi-
and control groups in terms of age, number of teeth, cantly reduced the plasma levels of CRP, IL-6, and fi-
gender, race, mean body mass index (BMI), systolic brinogen in patients with arterial hypertension. To our
and diastolic blood pressures, percentage of smokers, knowledge, this is the first study to show reduction of
percentage of persons from a low socioeconomic class, the inflammatory markers CRP, IL-6, and fibrinogen
or percentage of patients with generalized chronic after periodontal treatment, at the same time observa-
periodontitis (Table 1). tion (i.e., at 3 months). Our data showing a reduction
At baseline, there were no significant differences in in CRP is in line with other studies.29,31,35-38 Con-
the clinical periodontal data between the test and con- versely, Ide et al.32 and Yamazaki et al.39 did not show
trol groups. The mean percentage of sites with BOP, significant reductions in CRP levels. Significant reduc-
PD 4 to 5 mm, PD ‡6 mm, CAL 4 to 5 mm, and tions in the plasma levels of IL-6 were observed by
CAL ‡6 mm was significantly reduced in the test group D’Aiuto et al.,31 Elter et al.,20 and Higashi et al.,38
but not by Ide et al.32 and Yamazaki et al.39 Fibrinogen
Table 1. levels were not decreased in the studies by Mattila
et al.,35 Ide et al.,32 and Montebugnoli et al.37 The in-
Distribution of Variables in the Test and terval between blood collection varied between 1 and
Control Groups 6 months, which may have affected the results for the
different markers. CRP was not reduced 6 weeks after
Test Group Control Group P periodontal therapy in the study by Ide et al.,32 al-
Variable (n = 11) (n = 11) Value* though Mattila et al.35 reported a reduction in CRP
Age (years; mean [SD]) 48.9 (3.9) 49.7 (6.0) 0.71 levels in this same interval. Iwamoto et al.36 collected
blood 1 month after periodontal therapy and observed
Male (%) 55.5 63.6 1.0 significant reductions in CRP, whereas Elter et al.20 re-
Black (%) 28 28 1.0 ported a trend in the reduction of serum levels of CRP
during this interval. D’Aiuto et al.31 and Higashi et al.38
Smokers (%) 18.2 18.2 1.0 observed reductions in CRP only after 6 months. IL-6
Low socioeconomic 100 100 1.0 levels were significantly reduced 1,20 2, and 6
class (%) months31,38 after periodontal treatment. However,
Ide et al.32 and Yamazaki et al.39 reported no signifi-
Generalized chronic 72.7 72.7 1.0 cant reductions in IL-6 levels 6 weeks and 3 months
periodontitis (%) after periodontal treatment, respectively. Stud-
Systolic BP (mm Hg; 176.4 (25.4) 188.2 (38.2) 0.41 ies32,35,37 that evaluated fibrinogen levels collected
mean [SD]) blood samples 6 weeks and 3 months after periodon-
tal treatment and did not find significant changes.
Diastolic BP (mm Hg; 113.6 (16.3) 118.2 (24.0) 0.61
In the present study, we collected blood samples
mean [SD])
3 months after periodontal therapy because this is
BMI (kg/m2; mean [SD]) 31.0 (5.7) 29.6 (5.6) 0.56 considered an ideal time to evaluate periodontal heal-
ing after non-surgical periodontal treatment.40 Signif-
Teeth (n; mean [SD]) 20.2 (6.9) 18.6 (5.6) 0.55
icant reductions in CRP, IL-6, and fibrinogen plasma
BP = blood pressure.
* There were no significant differences between test and control groups at
baseline. ** SPSS 11.0, SPSS, Chicago, IL.

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J Periodontol • May 2009 Vidal, Figueredo, Cordovil, Fischer

Table 2.
Clinical Variables (% of sites; mean – SD) in the Test and Control Groups at Baseline
and 3 Months

Test Group (n = 11) Control Group (n = 11)

Variable Baseline 3 Months P1 Baseline 3 Months P2 P3

Visible plaque 59.4 (26.6) 49.4 (17.6) 0.260 65.8 (24.4) 60.8 (29.1) 0.59 0.56

BOP 45.7 (18.2) 19.4 (11.4) 0.002 42.7 (15.1) 40.3 (12.2) 0.44 0.68
PD 4 to 5 mm 19.5 (9.1) 4.9 (3.2) 0.000 19.2 (8.2) 17.8 (9.5) 0.18 0.93
PD ‡6 mm 8.1 (9.1) 1.2 (0.9) 0.025 5.6 (4.2) 5.6 (4.1) 0.96 0.42

CAL 4 to 5 mm 23.7 (8.9) 18.4 (10.1) 0.014 28.4 (11.9) 25 (9.5) 0.14 0.31
CAL ‡6 mm 24.5 (22.4) 11.2 (14.9) 0.002 18.9 (15.8) 19 (18.1) 0.86 0.50
P1 = difference between baseline and 3 months after periodontal therapy for test group; P2 = difference between baseline and 3 months for control group; P3 =
difference between test and control groups at baseline.

Table 3.
Plasma Levels of CRP, Fibrinogen, and IL-6 at Baseline and 3 Months

Test Group (n = 11) Control Group (n = 11)

CRP (mg/dl) Fibrinogen (mg/dl) IL-6 (pg/ml) CRP (mg/dl) Fibrinogen (mg/dl) IL-6 (pg/ml)

Patient Baseline 3 Months Baseline 3 Months Baseline 3 Months Patient Baseline 3 Months Baseline 3 Months Baseline 3 Months

1 1.49 1.35 376 360 234 87.6 1 0.71 2.99 331 490 5.8 6.8
2 0.38 0.15 494 376 2.1 1.0 2 0.09 0.1 512 490 9.0 9.2
3 0.70 0.30 318 312 1.0 1.0 3 0.03 0.04 253 254 1.0 1.0

4 0.49 0.06 252 258 1.0 1.0 4 0.03 0.07 283 276 1.0 1.0
5 2.95 1.05 385 372 5.1 2.0 5 1.07 1.78 372 360 1.0 7.6
6 1.07 1.19 497 380 4.1 1.0 6 0.82 1.49 380 376 54.4 234

7 0.51 0.61 423 396 5.9 7.4 7 0.61 0.49 276 253 1.0 1.0
8 0.36 0.25 376 231 3.3 1.0 8 0.98 2.95 372 385 1.0 5.1
9 1.36 1.39 364 332 2.5 1.0 9 0.68 1.07 372 497 1.0 4.1

10 2.81 0.39 505 490 2.4 1.0 10 0.15 0.23 372 396 1.0 1.0
11 2.99 2.93 490 322 6.8 6.1 11 0.68 1.36 376 364 1.0 2.5
Mean (SD) 1.4 0.9 407 348 24.4 10 0.5 1.1 354 376 7.0 24.9
(1.0) (0.8)* (82) (70)† (69.5) (25.8)† (0.4) (1.1)‡ (70) (90) (15.9) (69.4)‡
* Significantly lower than baseline value (P = 0.005).
† Significantly lower than baseline value (P = 0.03).
‡ Significantly higher than baseline value (P = 0.01).

levels were observed. The baseline values of inflam-
matory markers, susceptibility of the patients, selec-
tion criteria of the studied population, and differences
in the severity of periodontal disease may explain
some of the discrepancies in the results compared
to previous studies.
All clinical parameters improved after non-surgical
periodontal therapy except for the percentage of sites
with visible dental plaque, probably because oral hy-
giene instructions were only provided at the first visit.
However, the mean percentage of sites with BOP, PD,
and CAL improved after 3 months of periodontal

789
Periodontal Therapy in Refractory Arterial Hypertension
treatment, indicating that the treatment performed
was effective.
Periodontitis is a low-grade chronic inflammatory
disease that affects 35% to 60% of the adult popula-
tion; severe forms may affect 10% to 15% of the pop-
ulation.41 Its prevention and treatment may have an
impact on the control of chronic diseases related to in-
flammation, such as hypertension. The causes of re-
fractory hypertension include biologic factors (e.g.,
obesity), inaccurate blood pressure measurement,
non-compliance with prescribed medications, and
inadequate treatment.42 These causes may not be
important in the present study because the patients
were under regular medical control and had been en-
gaged in a maintenance program for ‡5 years. Despite
taking medications, they had high blood pressure
levels. The long-term benefits of reducing inflamma-
tory markers and acute-phase proteins in hyperten-
sive patients are unknown. The permanent control of
periodontal inflammation may allow for better control
of pressoric levels, a reduction in left ventricle mass,43
and a slowdown of the atherosclerotic process, leading
to a reduction in the patient’s cardiovascular risk.
Limitations of this study include a relatively small
sample size, which may affect the reproducibility of the
results, and the short observation period (3 months).
Prospective studies with a larger sample size and
longer observation periods are required to evaluate
the benefits of reducing these inflammatory markers
as a way of decreasing the global cardiovascular risk
for patients with arterial hypertension.
CONCLUSION
Non-surgical periodontal therapy was effective in
improving periodontal clinical data and reducing the
plasma levels of IL-6, CRP, and fibrinogen in hyper-
tensive patients with severe periodontitis.
ACKNOWLEDGMENTS
The authors are grateful to Dr. Constante Ramos,
Dr. Marcelo Barros, and Ana Beatriz Lima, social as-
sistant, National Institute of Cardiology, for their assis-
tance with the study. This study was supported by the
Rio de Janeiro State Research Foundation (FA-
PERJ), Rio de Janeiro, RJ, Brazil (E-26/111439/
2008), and Rio de Janeiro State University, Rio de
Janeiro, RJ, Brazil. The authors report no conflicts of
interest related to this study.
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Correspondence: Dr. Ricardo Guimarães Fischer, Faculty
of Odontology, Rio de Janeiro State University, Boulevard
28 de Setembro, 157, Vila Isabel, Rio de Janeiro 20551-
030, RJ, Brazil. Fax: 55-21-25234298; e-mail: ricfischer@
globo.com.
Submitted September 10, 2008; accepted for publication
December 24, 2008.
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