jurnal

1. Vol:.(1234567890)
Heart Vessels (2018) 33:198–204
https://doi.org/10.1007/s00380-017-1042-z
1 3
ORIGINAL ARTICLE
Specific periodontopathic bacterial infection affects hypertension
in male cardiovascular disease patients
Norio Aoyama1
· Jun‑ichi Suzuki2,3
· Hidetoshi Kumagai2
· Yuichi Ikeda5
·
Hiroshi Akazawa5
· Issei Komuro5
· Masato Minabe1
· Yuichi Izumi4
· Mitsuaki Isobe3
Received: 3 July 2017 / Accepted: 9 August 2017 / Published online: 12 August 2017
© Springer Japan KK 2017
pocket depth of elderly male patients with HT was higher
compared to non-HT patients. The rates of obesity, dys-
lipidemia, and diabetes showed partial statistical differ-
ence between the two groups. Specific periodontopathic
bacterial infection may affect HT in male cardiovascular
patients.
Keywords Bacteria · Hypertension · Cardiovascular
disease · Periodontal disease
Introduction
Periodontitis is a common oral disease that induces
destruction of the supporting tissues of teeth and finally
leads to tooth loss. It is characterized as a chronic infection
with periodontopathic bacteria. Studies have shown that
periodontitis has a high prevalence all over the world [1,
2]. Periodontitis is considered as a possible risk factor for
several systemic diseases such as cardiovascular disease
(CVD) [3]. Because CVD represents a fundamental cause
of death, prevention and treatment of CVD are an impor-
tant health issue. Many studies showed that periodontitis
patients were at a high risk for CVD events such as coro-
nary artery disease (CAD), stroke, and peripheral arterial
disease [4–10].
Hypertension (HT) is the most prevalent disorder among
CVDs [11]. Moreover, it was indicated that HT was involved
in approximately 50% of deaths due to CVD [12, 13]. A
relationship between HT and periodontitis was suggested
[14]; however, the precise effect of periodontopathic bacte-
rial infection on HT has not yet been clarified. The purpose
of this study was to assess the association between periodon-
topathic bacterial infection and HT in the adult Japanese
population with CVD.
Abstract Hypertension (HT) is a systemic disorder
that results in the decline of quality of life and death.
While patients with periodontitis are at a high risk of
HT, little causal information has been provided to date.
To clarify the relationship, periodontopathic bacterial
infection in cardiovascular patients with or without HT
was evaluated. The subjects were patients with (n = 412)
or without (n = 199) HT who attended Tokyo Medical
and Dental University hospital. Blood examinations
and periodontal measurements were performed. Three
periodontopathic bacteria existence and antibody titers
were evaluated. We found that specific periodontopathic
bacteria, Aggregatibacter actinomycetemcomitans and
Prevotella intermedia, were highly detected in male sub-
jects with HT compared to non-HT subjects, while they
were comparable in the female patients. Mean probing
* Jun‑ichi Suzuki
junichisuzuki‑circ@umin.ac.jp
1
Division of Periodontology, Department of Oral
Interdisciplinary Medicine, Graduate School of Dentistry,
Kanagawa Dental University, 82 Inaokacho, Yokosuka,
Kanagawa 238‑8580, Japan
2
Department of Advanced Clinical Science and Therapeutics,
The University of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku,
Tokyo 113‑8655, Japan
3
Department of Cardiovascular Medicine, Tokyo Medical
and Dental University, 1‑5‑45 Yushima, Bunkyo‑ku,
Tokyo 113‑8549, Japan
4
Department of Periodontology, Graduate School of Medical
and Dental Sciences, Tokyo Medical and Dental University,
1‑5‑45 Yushima, Bunkyo‑ku, Tokyo 113‑8549, Japan
5
Department of Cardiovascular Medicine, The University
of Tokyo, 7‑3‑1 Hongo, Bunkyo‑ku, Tokyo 113‑8655, Japan

2. 199Heart Vessels (2018) 33:198–204
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Materials and methods
Study population
Subjects who were 61–80 years were recruited from patients
with CVD of the Department of Cardiovascular Medicine
in Tokyo Medical and Dental University Hospital between
May 2012 and August 2015. Six hundred and eleven sub-
jects were enrolled and subdivided into four groups (61–70
male, 61–70 female, 71–80 male, and 71–80 female) in this
study. Patients who did not consent to the participation in
this study or had a history and/or presence of other infec-
tions were excluded. The Ethics Committees of the School
of Medicine and the School of Dentistry, Tokyo Medical
and Dental University approved the protocol of the present
study, and the protocol conformed to the Helsinki Declara-
tion of 1975, as revised in 2013. Written informed consent
was provided by each subject.
Diagnosis of patients in this study were as follows: 321
arrhythmia, 188 angina pectoris, 79 myocardial infarction,
78 heart failure, 73 valvular disease, and 36 cardiomyopa-
thy. In case a subject had several CVDs, each disease was
counted.
Medical examination
A medical history was recorded and a physical examination
was performed. Subjects who were diagnosed and/or treated
as HT, diabetes mellitus (DM), dyslipidemia (DL), and obe-
sity in the department were recorded. Smoking history was
obtained by interview. Peripheral blood samples were col-
lected, centrifuged at 1500×g for 20 min, and then stored at
−20 °C until analysis. Laboratory parameters determined
from serum samples included concentrations of low-density
lipoprotein cholesterol (LDL-c), hemoglobin A1c (HbA1c),
and C-reactive protein (CRP).
Clinical periodontal examination
As a periodontal examination, probing pocket depth (PPD),
clinical attachment level (CAL), and bleeding on probing
(BOP) were measured at six points (buccal–mesial, mid-
buccal, buccal–distal, lingual–mesial, mid-lingual, and lin-
gual–distal) on a right upper molar, an upper incisor, a left
upper molar, a right lower molar, a lower incisor, and an left
lower molar with a manual probe (PCP-UNC 15, Hu-Friedy,
Chicago, IL, USA). The next tooth was used when the rep-
resentative tooth was missing.
Bacterial identification
Unstimulated saliva and subgingival plaque samples, with
30-s insertion of a sterile #40 paper point into the deepest
periodontal pocket among the recorded teeth, were obtained.
Bacterial DNA was extracted from 200-µl saliva and the
subgingival plaque using DNeasy Blood and Tissue kit
(Qiagen, Tokyo, Japan) according to manufacturer’s instruc-
tions. Real-time polymerase chain reaction (PCR) method
was used to detect three periodontopathic bacteria (Porphy-
romonas gingivalis, Aggregatibacter actinomycetemcomi-
tans, and Prevotella intermedia). The real-time PCR was
performed as described previous report [15]. Specific prim-
ers for each bacterium were used as previously described
[16]. Positive rate of each bacterium in saliva and subgingi-
val pocket was calculated.
Anti‑bacterial antibodies
Serum samples were analyzed for IgG antibody against cell
surface antigens for the periodontal pathogens, P. gingi-
valis, A. actinomycetemcomitans, and P. intermedia, using
an enzyme-linked immunosorbent assay (ELISA) as previ-
ously described [17]. The absorbance of each well was read
using a microplate reader at 450 with a 650-nm reference
wavelength. Individual serum antibody levels (Units/mL)
were calculated from the standard curve obtained from the
gradual dilutions of the reference.
Data analysis
Numerical data were presented as mean ± standard deviation
(SD). Student’s t test was used to compare age, CRP, LDL-c,
HbA1c, PPD, CAL, and BOP. Chi-square test was performed
to compare smoker rate, presence of DM, DL, and obesity,
and positive rate of each bacterium. Wilcoxon test was used
to compare anti-bacterial antibodies. Multivariate analyses
were performed, using logistic regression, calculating crude
and adjusted odds ratios with their 95% confidence intervals.
For these analyses, we used a model that includes several
confounding factors such as DM, DL, obesity, and LDL-c.
JMP 9.0.3 (SAS Institute Inc., Cary, NC, USA) was used for
all statistical analyses. Values of p < 0.05 were considered
significant.
Results
Patient’s characteristics and blood data
The characteristics of the subjects and blood data in this
study are shown (Table 1). At first, we analyzed data of
the whole subjects and found that differences of age and
sex were detected between the HT and non-HT groups
(Table 1a). Then, we subdivided the subjects into four
groups (61–70 male, 61–70 female, 71–80 male, and
71–80 female). After the division, there was no statistical

3. 200 Heart Vessels (2018) 33:198–204
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difference in age and smoker rate between the HT and
non-HT groups. The 71–80-year-old female HT patients
had a higher prevalence of DM compared to the non-HT
patients, while HbA1c levels were comparable between
the two groups (Table 1d). The 61–80-year-old male HT
patients had a higher prevalence of DL compared to the
non-HT patients; however, LDL-c levels were comparable
(71–80-year-old male) or lower (61–70-year-old male) in
HT group (Table 1c, e). A higher obesity rate was detected
in male HT subjects than non-HT subjects, while female
patients also showed significant difference (61–70 years)
or just tendency (71–80 years) in obesity rates between
the two groups. CRP and HbA1c levels were comparable
between the groups in all age categories.
Oral conditions
Periodontal conditions of the subjects in each category are
shown in Figs. 1, 2, and 3. PPD of 71–80-year-old men
with HT was deeper than that of non-HT subjects (Fig. 1).
There was no statistical difference of CAL (Fig. 2) and
BOP (Fig. 3) between HT and non-HT patients in all
categories.
Table 1 Characteristics of total patients (a), 61–70-year-old female
(b), 61–70-year-old male (c), 71–80-year-old female (d), and
71–80-year-old male subjects (e)
HT Non-HT p
(a)
Number 412 199
Age 70.7 ± 5.3 68.7 ± 5.2 <0.0001
Sex (female %) 24 34 0.0130
Smoker (%) 49 39 0.0218
Diabetes mellitus (%) 35 20 <0.0001
Dyslipidemia (%) 55 35 <0.0001
Obesity (%) 26 9 <0.0001
CRP (mg/dL) 0.40 ± 1.17 0.38 ± 1.64 NS
LDL-c (mg/dL) 102.5 ± 29.2 114.7 ± 31.0 <0.0001
HbA1c (%) 6.1 ± 0.8 6.0 ± 0.8 NS
(b)
Number 42 47
Age 66.2 ± 2.7 66.2 ± 3.2 NS
Smoker (%) 17 9 NS
Diabetes mellitus (%) 17 9 NS
Dyslipidemia (%) 62 45 NS
Obesity (%) 24 9 0.0456
CRP (mg/dL) 0.25 ± 0.63 0.15 ± 0.43 NS
LDL-c (mg/dL) 119.9 ± 28.9 119.4 ± 26.2 NS
HbA1c (%) 6.0 ± 0.9 5.7 ± 0.7 NS
(c)
Number 147 85
Age 65.6 ± 2.9 65.3 ± 2.9 NS
Smoker (%) 61 54 NS
Diabetes mellitus (%) 30 19 NS
Dyslipidemia (%) 56 31 0.0001
Obesity (%) 27 9 0.0007
CRP (mg/dL) 0.29 ± 0.60 0.37 ± 0.90 NS
LDL-c (mg/dL) 104.0 ± 28.9 114.8 ± 31.9 0.0112
HbA1c (%) 6.1 ± 0.7 6.0 ± 0.7 NS
(d)
Number 57 20
Age 74.6 ± 2.4 74.7 ± 2.9 NS
Smoker (%) 16 30 NS
Diabetes mellitus (%) 33 10 0.0307
Dyslipidemia (%) 65 45 NS
Obesity (%) 30 15 NS
CRP (mg/dL) 0.28 ± 0.51 1.33 ± 4.68 NS
LDL-c (mg/dL) 102.2 ± 30.5 135.4 ± 36.1 0.0005
HbA1c (%) 6.2 ± 1.1 6.1 ± 0.8 NS
(e)
Number 166 47
Age 74.9 ± 2.8 74.7 ± 2.6 NS
Smoker (%) 58 47 NS
Diabetes mellitus (%) 44 36 NS
Dyslipidemia (%) 49 28 0.0087
Obesity (%) 25 6 0.0026
Table 1 (continued)
HT Non-HT p
CRP (mg/dL) 0.57 ± 1.69 0.24 ± 0.50 NS
LDL-c (mg/dL) 96.6 ± 27.4 101.8 ± 26.5 NS
HbA1c (%) 6.1 ± 0.8 6.1 ± 0.8 NS
HT hypertension, CRP C-reactive protein, LDLc low-density lipopro-
tein cholesterol, HbA1c hemoglobin A1c
Fig. 1 Mean number of mean PPD is shown. Data are presented as
mean ± SD. *p < 0.05 between HT and non-HT groups

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Bacterial existence and antibody levels
The detection rate of bacteria is shown in Table 2. We
found an increased A. actinomycetemcomitans-positive
rate of 61–70-year-old male HT patients in both saliva and
subgingival plaque in comparison with non-HT patients
(Table 2c). P. intermedia was also highly detected in sub-
gingival samples of 71–80-year-old male subjects with HT
compared to non-HT subjects (Table 2e). A positive rate
of P. gingivalis was similar in both saliva and subgingival
plaque between HT and non-HT patients in all age or gen-
der categories. There was no statistical difference in serum
antibody levels to the periodontal bacteria between the HT
and non-HT groups (data not shown).
In Table 3, we performed multiple logistic regression
analysis to assess whether HT patients had a high detection
rate of bacteria regardless of confounding factors such as
DM, DL, and obesity. We found that 71–80-year-old male
HT patients had a high detection rate of P. intermedia after
adjustment of DM, DL, and obesity.
Discussion
In this study, we revealed that more severe periodontitis
was observed in HT subjects compared to non-HT subjects
in CVD patients. We also found that specific periodonto-
pathic bacteria, A. actinomycetemcomitans and P. interme-
dia, were highly detected in male HT subjects compared to
non-HT subjects. A high detection rate of P. intermedia in
71–80-year-old male patients was observed after adjustment
of DM, DL, and obesity.
Periodontitis affects HT
It is well known that there is a relationship between peri-
odontitis and HT. It has been shown that periodontitis was
associated with the presence of HT, which suggested that the
risk for HT increased, especially in people, whose chronic
periodontitis had not been treated [18]. Martin-Cabezas et al.
[19] mentioned that the prevalence of HT was statistically
associated with the presence of periodontal diseases. They
indicated that periodontal disease, especially severe peri-
odontitis, was associated with a risk of HT. However, there
has been no report to compare the existence of specific peri-
odontopathic bacteria between HT and non-HT patients. We
previously reported that antibody levels in specific periodon-
topathic bacteria were associated with a risk of CAD [17].
In that paper, we showed that antibody titers to A. actino-
mycetemcomitans and P. intermedia were associated with a
higher risk of CAD. Because HT is a major risk factor of
CAD, specific bacterial infection may deteriorate HT and
result in CAD onset.
Specific periodontopathic bacteria infection may
deteriorate HT
Aggregatibacter actinomycetemcomitans is known to affect
the pathogenesis of atherosclerosis, such as lipoprotein
serum concentration, endothelial permeability, and binding
of lipoproteins in the arterial intima [20]. Straka et al. dem-
onstrated that the proportion of CRP and IL-6 positive val-
ues was significantly higher in A. actinomycetemcomitans-
positive patients than in A. actinomycetemcomitans-negative
patients with CVD. They concluded that the presence of
A. actinomycetemcomitans in patients with CVD might
be associated with significantly increased serum levels of
some proinflammatory markers [21]. We also reported that a
serum antibody level against P. intermedia was significantly
higher in the CAD group than in the non-CAD group. The
levels were significantly correlated with the vector scores
Fig. 2 Mean number of mean CAL is shown. Data are presented as
mean ± SD
Fig. 3 Mean number of mean BOP rate is shown. Data are presented
as mean ± SD

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of the number of sites with probing depth ≥6.0 mm and
the composite periodontal risk scores [22]. Oliveira et al.
showed that P. intermedia was found in the cardiac valve
samples of 19.1% patients with heart valve disease, who
also had a high rate of periodontitis [23]. Further studies are
needed to explore the effects of A. actinomycetemcomitans
and P. intermedia on the etiology of HT.
Pathophysiologic mechanism
To date, several pathophysiological pathways have been
proposed as potential links between periodontal disease
and CVD. Although transient bacteremia and systemic
inflammation are focused on as factors which can mediate
interaction between periodontitis and CVD, their underlying
mechanism has not yet been clarified [24]. Macedo Paizan
et al. proposed possible pathophysiologic mechanisms
between periodontal disease and HT. They suggested that
endothelial and vascular dysfunction presented by peri-
odontal disease may lead to increased blood pressure [25].
Because it was showed that periodontal treatment induced
improvement in endothelial function [26], endothelial dys-
function led by periodontal infection can be an accelerator
of blood pressure. Oxidative stress also has the potential to
connect periodontitis and HT. Periodontitis subjects have
high levels of local and systemic biomarkers of oxidative
Table 2 Positive rates of
bacteria in total patients (a),
61–70-year-old female (b),
61–70-year-old male (c),
71–80-year-old female (d), and
71–80-year-old male subjects
(e)
HT hypertension
Group HT Non-HT p
(a)
P. gingivalis positive rate in saliva (%) 77 71 NS
A. actinomycetemcomitans-positive rate in saliva (%) 18 17 NS
P. intermedia positive rate in saliva (%) 30 27 NS
P. gingivalis positive rate in subgingival plaque (%) 73 67 NS
A. actinomycetemcomitans-positive rate in subgingival plaque (%) 16 14 NS
P. intermedia positive rate in subgingival plaque (%) 27 20 0.0391
(b)
P. gingivalis positive rate in saliva (%) 82 65 NS
A. actinomycetemcomitans-positive rate in saliva (%) 18 25 NS
P. intermedia positive rate in saliva (%) 38 25 NS
P. gingivalis positive rate in subgingival plaque (%) 73 54 NS
A. actinomycetemcomitans-positive rate in subgingival plaque (%) 11 20 NS
P. intermedia positive rate in subgingival plaque (%) 22 17 NS
(c)
P. gingivalis positive rate in saliva (%) 76 72 NS
A. actinomycetemcomitans-positive rate in saliva (%) 22 11 0.0495
P. intermedia positive rate in saliva (%) 33 29 NS
P. gingivalis positive rate in subgingival plaque (%) 71 72 NS
A. actinomycetemcomitans-positive rate in subgingival plaque (%) 18 6 0.0125
P. intermedia positive rate in subgingival plaque (%) 33 24 NS
(d)
P. gingivalis positive rate in saliva (%) 64 76 NS
A. actinomycetemcomitans-positive rate in saliva (%) 17 24 NS
P. intermedia positive rate in saliva (%) 26 41 NS
P. gingivalis positive rate in subgingival plaque (%) 71 84 NS
A. actinomycetemcomitans-positive rate in subgingival plaque (%) 16 26 NS
P. intermedia positive rate in subgingival plaque (%) 20 32 NS
(e)
P. gingivalis positive rate in saliva (%) 80 70 NS
A. actinomycetemcomitans-positive rate in saliva (%) 15 18 NS
P. intermedia positive rate in saliva (%) 27 18 NS
P. gingivalis positive rate in subgingival plaque (%) 76 63 NS
A. actinomycetemcomitans-positive rate in subgingival plaque (%) 16 15 NS
P. intermedia positive rate in subgingival plaque (%) 26 7 0.0051

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stress. Oxidative stress accompanied by an excess activity
of reactive oxygen species may play a role not only in peri-
odontal tissue destruction but also in circulation control [27,
28].
Study limitation
In this study, we showed the statistical difference of DM,
DL, and obesity in some groups. The 71–80-year-old female
HT patients had a higher prevalence of DM than non-HT
patients, while HbA1c levels were comparable between the
two groups. Because all generation groups had comparable
HbA1c levels, DM was appropriately treated in this study
population. Male HT patients had a higher prevalence of DL
compared to men without HT; however, LDL-c levels were
comparable (71–80-year-old males) or lower (61–70-year-
old males) in the HT group. Because the HT group had
comparable or lower LDL-c levels compared to the non-HT
group, DL seemed to be also appropriately treated in the HT
group. Thus, the specific bacterial infection may not affect
HT via DM or DL. A higher obesity rate was detected in
male HT subjects compared to non-HT subjects, and female
patients also showed significant difference (61–70 years)
or tendency (71–80 years) in obesity rate between the two
groups. If obesity enhanced bacterial infection, both the
male and female populations should have shown the same
significance. Thus, obesity may not be associated with the
bacterial infection. Further analysis is needed to clarify the
causal relationship among the factors.
Conclusion
We revealed that specific periodontopathic bacteria, A.
actinomycetemcomitans and P. intermedia, were highly
detected in male subjects with HT compared to non-HT
subjects. Thus, we can conclude that specific periodonto-
pathic bacterial infection may affect HT in male cardiovas-
cular patients. Further investigation is needed to reveal the
detailed causal relationship between HT and specific peri-
odontopathic bacterial infection.
Acknowledgements The authors wish to thank Dr. Naho Kobayashi,
Dr. Tomoya Hanatani, Dr. Norihiko Ashigaki, Dr. Yuka Shiheido,
Dr. Makoto Kaneko, Dr. Hiroki Sato, Dr. Katsuhiko Matsuo, and Dr.
Chisato Takamura for excellent assistance. This work was supported
by JSPS KAKENHI Grant Numbers (JP25870198 and JP16H05824),
Ministry of Education, Culture, Sports, Science and Technology of
Japan, Mitsui Life Insurance Research Foundation, Mitsui Sumitomo
Marine Welfare Research Foundation, Geriatric Dental Research
Foundation, Human Health Future Research Foundation, St. Luke’s
Hospital Research Foundation, Health Management Foundation, Taiyo
Life Insurance Research Foundation, The 8020 Promotion Founda-
tion, Terumo Science Foundation, Pfizer Health Research Foundation,
General Health Promotion Foundation, Suzuken Memorial Foundation,
Health Science Center Foundation, Kobayashi International Scholar-
ship Foundation, and Hakujikai Institute of Gerontology Foundation.
Compliance with ethical standards
Conflict of interest All authors declared that they have no potential
conflict of interest.
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Odds ratios for (a) Aggregatibacter actinomycetemcomitans detec-
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#
Adjusted for diabetes mellitus, dyslipidemia, and obesity
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#
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