| |

Received: 1 September 2021    Revised: 12 April 2022    Accepted: 15 May 2022

DOI: 10.1111/jre.13021

ORIGINAL ARTICLE

Cross-­sectional analysis of the association of periodontitis with

carotid intima media thickness and atherosclerotic plaque in
the Hamburg City health study

Ragna Lamprecht1 | David Leander Rimmele2 | Renate B. Schnabel3,4 |

Guido Heydecke1 | Udo Seedorf1 | Carolin Walther1  | Carola Mayer2 |
Julia Struppek1 | Katrin Borof1,5 | Christian-­Alexander Behrendt6 | Bastian Cheng2 |
Christian Gerloff2 | Sebastian Debus6 | Ralf Smeets7,8 | Thomas Beikler9 |
Stefan Blankenberg3,4 | Tanja Zeller3,4 | Mahir Karakas3,4 | Götz Thomalla2 |
Ghazal Aarabi1
1
Department of Prosthetic Dentistry, Center for Dental and Oral Medicine, University Medical Center Hamburg-­Eppendorf, Hamburg, Germany
2
Department of Neurology, University Medical Center Hamburg-­Eppendorf, Hamburg, Germany
3
Department of Cardiology, University Heart and Vascular Center, Hamburg, Germany
4
German Center for Cardiovascular Research (DZHK), Partner Site Hamburg/Lübeck/Kiel, Munich, Germany
5
Epidemiological Study Center, University Medical Center Hamburg-­Eppendorf (UKE), Hamburg, Germany
6
Department of Vascular Medicine, University Medical Center Hamburg-­Eppendorf, Hamburg, Germany
7
Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-­Eppendorf, Hamburg, Germany
8
Division of “Regenerative Orofacial Medicine”, Department of Oral and Maxillofacial Surgery, University Medical Center Hamburg-­Eppendorf, Hamburg,
Germany
9
Department of Periodontics, Preventive and Restorative Dentistry, University Medical Center Hamburg-­Eppendorf, Hamburg, Germany

Correspondence
Ghazal Aarabi, Department of Prosthetic
Dentistry, Center for Dental and Oral
Medicine, University Medical Center
Hamburg-­Eppendorf, Martinistrasse 52,
20251 Hamburg, Germany.
Email: g.aarabi@uke.de
Funding information
GA has received funding from the Else
Kröner-­Fresenius Foundation (2016_
A166).
Abstract
Background: Previous epidemiological studies regarding the association between
chronic periodontitis (CP) and carotid intima-­media thickness (cIMT) and subclinical
atherosclerosis have been inconclusive.
Objective: The aim of this study was to determine whether CP is associated with sub-
clinical atherosclerosis in a large population-­based cohort study conducted in north-
ern Germany (the Hamburg City Health study).
Methods: Baseline data from 5781 participants of the Hamburg City Health Study
with complete oral health and carotid ultrasound data (50.7% female, mean age:
62.1  ± 8.4 years) were evaluated. A standardized duplex sonography of the carotid
artery was performed with measurement of carotid intima-­media thickness (cIMT)
and atherosclerotic plaques. Oral health was assessed by recording the decayed, miss-
ing, and filled teeth (DMFT) index, clinical attachment loss (CAL), bleeding on probing

Ragna Lamprecht and David Leander Rimmele contributed equally to this work.

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction
in any medium, provided the original work is properly cited and is not used for commercial purposes.
© 2022 The Authors. Journal of Periodontal Research published by John Wiley & Sons Ltd.

J Periodont Res. 2022;00:1–11.  |

wileyonlinelibrary.com/journal/jre     1
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2      LAMPRECHT et al.

(BOP), and the dental plaque index (PI). Correlations were tested for statistical signifi-
cance by means of descriptive statistics and multivariate regression analyses.
Results: Moderate and severe CP were associated with the prevalence of cIMT ≥ 1 mm
(none or mild CP: 5.1%, moderate CP: 6.1%, severe CP: 10%) and mean cIMT (none or
mild CP: 0.72 mm, moderate CP: 0.75 mm, severe CP: 0.78 mm) in bivariate analyses
(p < .001). Additionally, severe and moderate CP were associated with higher preva-
lence of carotid atherosclerotic plaques (plaque = yes: none or mild CP: 23.9%, mod-
erate CP: 29%, severe CP: 40.2%,). After adjustment for age, sex, smoking, diabetes,
hypertension, educational level, hypercholesterolemia, and hsCRP, severe CP still cor-
related significantly with cIMT and the prevalence of cIMT ≥1 mm and/or presence of
carotid atherosclerotic plaques.
Conclusion: In this study, severe CP was associated with increased cIMT and higher
prevalence of carotid plaques independent of common risk factors.

KEYWORDS
atherosclerosis, epidemiology, intima-­media-­thickness, periodontitis, plaque, ultrasound

1  |  I NTRO D U C TI O N hypothesized that there is an association between CP and cIMT

Cardiovascular disease (CVD) is a common cause of morbidity and
1
mortality mainly due to atherosclerosis a highly prevalent chronic
condition of arterial vessel walls, which leads to changes in the
2
vascular intima associated with changes in the vascular media. A
chronic inflammatory reaction has been identified as an additional
risk factor in the initiation of atherosclerosis, especially in periph-
3
eral arteries. One hypothesis is that oral inflammation (e.g., chronic
periodontitis, CP) can modulate inflammatory events in atherogene-
sis via its systemic effects.4
CP, a chronic inflammatory disease of the soft and hard tissue
surrounding the tooth, is the 6th most common disease of the
5 6
human with a high overall prevalence of 45%–­50%. The oppor-
tunistic infection of the periodontium by anaerobic pathogenic
bacteria in the subgingival dental plaque leads to a destructive
host inflammatory response. By micro traumatizing the gingiva,
pathogenic bacteria can enter the bloodstream and colonize inter-
nal organs and blood vessels.7 Additionally, specific pro-­ and anti-­
inflammatory cytokines, small signal molecules and modulating
enzymes can modulate chronic inflammatory reactions that may
affect overall health. 8
Epidemiological studies showed that periodontal and cardio-
vascular diseases share common risk factors, such as higher age,
9,10
male sex, smoking, diabetes, and hypertension. Experimental
studies demonstrated that subclinical inflammatory changes of the
gingiva accelerate the accumulation of inflammatory markers and
modify the circulating monocytes to become pro-­atherogenic.11
In addition, chronic CP leads to the production of C-­reactive
protein (CRP) and fibrinogen in the liver via the formation of
pro-­inflammatory mediators, which in turn may stimulate ath-
erogenesis.4 In patients with severe CP, periodontal pathogens
12
were found in 42% of the examined atheromas. It is therefore
and that periodontal infection is an independent risk factor for
atherosclerosis and its clinical consequences.13-­15 Carotid intima-­
media thickness (cIMT) measures the thickness of the inner two
layers of the carotid artery—­t he intima and media—­and thickening
is a predictor of future cardiovascular events when patients are
still asymptomatic.16,17 Values ≥1 mm are considered pathological
(morbidly elevated)18 and indicate a strong change in the vessel
wall.19 Aging and male sex are strong predictors of increased cIMT.
Other risk factors are high LDL cholesterol, low HDL cholesterol,
high blood pressure, smoking, diabetes, obesity, and a sedentary
lifestyle. Although cIMT is a widely used surrogate marker for pre-
clinical atherosclerosis and may improve risk prediction, its use for
the clinical evaluation of cardiovascular disease risk is not recom-
mended by American Heart Association and European guidelines,
largely owing to conflicting results and a lack of standardization in
the assessment models.18 A recent study showed that the carotid
lumen diameter may represent a marginally better predictor of car-
diovascular and all-­c ause mortality than cIMT. 20
Previous studies showed that CP was associated with cIMT
≥1 mm in a multivariable logistic regression model adjusted
for cardiovascular risk factors in the Atherosclerosis Risk in
Communities (ARIC) study, which is a large US survey of men and
women aged 52–­75 years.10 A more recent meta-­a nalysis demon-
strated that the diagnosis of CP was associated with a significant
mean increase in cIMT compared with controls. 21 Additionally,
it could be demonstrated that the periodontal bacterial burden
was related to cIMT, which was specific for causative bacte-
ria and independent of CRP. 22 On the other hand, the associa-
tion between CP and cIMT observed in conventional regression
analyses might be due to collider bias stratification according to
Leite et al. 23 The authors observed a strong association between
CP and cIMT in participants with high CRP level but not in those
LAMPRECHT et al.
with CRP <3 mg/L. Additionally, a Chinese study observed a lin-
ear and dose-­d ependent association between periodontal mea-
sures including mean CAL, maximal cIMT, and carotid plaque load
only in elderly hyperglycemic subjects, whereas no association
could be detected in euglycemic subjects. 24 A recent Mendelian
randomization study to test whether CP is causally associated
with increased cIMT found no correlation for CP with subclini-
cal atherosclerosis. 25 Taken together, these more recent studies
raised the possibility that the association between CP and cIMT
observed in observational studies may largely be due to con-
founding. The ARIC sample, which so far has provided the stron-
gest support for an association between CP and increased cIMT
/ carotid plaque, was recruited and examined already more than
20 years ago (1996–­1998). Since then, the age-­a djusted incidence
rates of CVD endpoints and the prevalence of risk factors have
been decreasing, 26,27 most likely partly due to beneficial lifestyle
changes and improvements of medicine (i.e., medication with
statins, anti-­hypertensives, and anti-­d iabetics). The same pertains
to the age-­a djusted incidence rates of CP, which also follow de-
clining trends. 28 Thus, we were interested in re-­evaluating the po-
tential association between CP and subclinical atherosclerosis in
a large population-­b ased sample of middle-­a ged and elderly men
and women recruited between February 2016 and November
2018 with special emphasis on potential confounders including
CRP.
2  |   M E TH O D S
2.1  |  Study population, study design and setting
This cross-­sectional study was conducted as part of the Hamburg
City Health Study (HCHS) at the University Medical Center
29
Hamburg-­Eppendorf (UKE) in Hamburg, Germany. HCHS is an
ongoing, prospective, population-­based cohort study with a target
sample of 45 000 participants to identify risk factors and important
correlations of major chronic diseases. General inclusion criteria
are as follows: inhabitant of Greater Hamburg aged between 45
and 74 years (sampled randomly from records of the residents' reg-
istration office), adequate knowledge of the German language and
physical and psychological capability to participate. The study's ra-
tional and protocol, which includes validated examinations target-
ing major organ systems and several self-­report questionnaires, are
published. 29 For the current study, we evaluated baseline data of
the first 10 000 participants enrolled in the HCHS from February
2016 to November 2018. 6209 participants with completed peri-
odontal examination of which 5781 also had complete carotid ul-
trasound data were included (Figure 1)
This manuscript was prepared according to the STROBE
guidelines. 31 The study was carried out in accordance with the
Declaration of Helsinki. The study protocol of the HCHS was ap-
proved by the Ethics Committee of the Hamburg Chamber of phy-
sicians (PV5131). Written informed consent was obtained from all
|
      3
Included:
Excluded: 1. Enrolled in the HCHS: 2016-2019
(n = 10,000)
5. General exclusion criteria
n = 105 (1.1% of 1.)
2. Included in the HCHS: 2016-2019
(n = 9,895 (99.0% of 1.)
6. Periodontitis
classification not available
n = 3,791 (37.9% of 1.) 3. Periodontis classification available
n = 6,209 (62.1% of 1.)
7. cIMT
not available
n = 428 (6.9% of 3.) 4. Periodontitis classification and cIMT
available
n = 5,781 (93.1% of 3.)
F I G U R E 1  Sampling flow chart. General exclusion criteria were
<4 teeth and/or inadequate knowledge of the German language to
participate
participants prior to their enrollment. Participation in the study
was voluntary.
2.2  |  Variables
2.2.1  |  Dental examination
The dental examination was performed by trained and calibrated
non-­d ental staff with extensive experience in conducting the ex-
amination, which was performed according to a pre-­specified SOP
under the supervision of a dentist. The 49 examiners, who also
conducted the oral health examinations for the German National
Cohort (GNC) study, collected the raw data, such as number of
teeth, pocket depths, number of bleeding points on probing, which
were then used by two dentists to establish the diagnosis. In case
of disagreement, consensus was established by consulting a third
dentist. Data accuracy was established by regular training and
calibration of the staff in the pilot phase and while the study was
ongoing. Electronic data capture and transfer, longitudinal per-
formance evaluation, and statistical monitoring were performed
regularly during the study. The validity of the results obtained
by trained non-­d ental examiners was confirmed in a published
quality control study by Holtfreter et al. 31 on the basis of data
from the GNC study. The oral examination included the following
steps: CP was diagnosed as part of the dental examination with
a standardized periodontal probe (Hu-­f riedy, Chicago, USA) fol-
lowing a full mouth—­six sites protocol, excluding the third molars.
Decisive periodontal parameters were the probing depths (PCP)
and the gingival recessions, each of which was collected at 6 sites
per tooth. The respective CAL per tooth was calculated by adding
PCP and recession. The grading of CP in severity grades was based
on the criteria of Eke et al. 32 A four-­p oint ordinal scale was used
(no, mild, moderate, severe).
Additionally, the bleeding on probing (BOP) index was collected
per tooth (yes/no) and the plaque index (PI) of Silness-­Löe (1964)
of the periodontal tissue was collected at two sites per tooth.
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4      LAMPRECHT et al.
Subsequently, the DMFT-­index (D = decayed, M = missing, F = filled,
T = teeth) was calculated.
2.2.2  |  Assessment of carotid atherosclerosis
For the assessment of carotid atherosclerosis, the IMT of the com-
mon carotid artery was measured and the presence of atheroscle-
rotic plaques was recorded using B-­mode duplex sonography, which
was performed manually with a Siemens SC2000 Ultrasound System
equipped with a 5–­7.5 MHz broadband linear transducer. CIMT was
measured in both common carotid arteries with a distance of at least
1 cm from the bifurcation. The mean of these measures was taken
for further analysis. As a cut off for pathologic thickness, respec-
tively, atherosclerosis we chose values of 1 mm and above according
to the criteria of the European Stroke organization.34 Plaques were
defined as a focal thickness above 1.5 mm.
2.3  |  Confounders
Prior to the visit in the study center, all participants received a self-­
report questionnaire, which included questions regarding sociode-
mographic characteristics, such as age, nationality, sex, lifestyle, and
environmental conditions. During the baseline visit, the medical his-
tory of systemic diseases, previous vascular events, and medication
was evaluated. The level of education was classified according to the
International Standard Classification of Education (ISCED) criteria.35
Family history of cardiovascular disease was evaluated in a follow-­up
36
questionnaire.
Smoking behavior was assessed with the Fagerström ques-
tionnaire37 and each participant was classified as smoker, former
smoker, or never-­smoker. Blood pressure and heart rate were mea-
sured on the right arm after 5  min of rest, twice in sitting posi-
tion. The mean value of the two measurements was used for the
analyses. Hypertension was defined by systolic/diastolic values
above 140/90 mmHg, or participants' self-­report or antihyperten-
sive medication. Furthermore, a panel of basic laboratory analy-
ses was performed on the day of the visit in the study center for
measuring biomarkers, which included estimated, high-­s ensitivity
measured CRP (hsCRP), glucose, HDL-­cholesterol, and total cho-
lesterol. Hypercholesterolemia was defined as LDL-­cholesterol
equal or greater than 130 mg/dl or statin treatment. Regulation
of blood glucose metabolism was assessed by non-­f asting and
fasting glucose. Diabetes was defined as values of fasting glucose
above 126 mg/dl or non-­f asting above 200 mg/dl or participants'
self-­report.
2.4  |  Statistical analyses
Descriptive analyses were performed for all variables with calcu-
lation of frequency distributions for the categorical variables and
median (interquartile range [IQR]) were computed for continuous
variables, stratified by the status of CP. For the bivariate analyses,
p-­v alues were calculated by a chi square test for categorical vari-
ables and by a Kruskal–­Wallis test for continuous variables. The
associations between periodontal status parameters and cIMT
adjusted for confounders were tested using simple and multivari-
able linear or logistic regression analyses. As the mild periodon-
titis group was rather small (n  =  69) and as there is practically
no clinically difference between no and mild periodontitis, this
group was merged with the large no periodontitis group for the
regression analyses. Five models were considered: 1 a crude un-
adjusted model, and 4 additional regression models including ad-
justments for age, sex, diabetes, smoking, hypertension, and/or
log hsCRP. Linear regression coefficients (β) or odds ratios (OR)
and their 95% confidence intervals (95%  CI) were reported de-
pending on the data format and values of p < .05 were considered
significant. All statistical analyses were performed using RStudio
Version 1.1.453.
3  |  R E S U LT S
3.1  |  Descriptive analysis
3.1.1  |  Characteristics of participants
A total of 6209 participants with complete periodontal data and a
mean age of 62.1 ± 8.4 years were analyzed. Baseline characteristics
of the study population (Table  1) were stratified by degree of CP
(none: n = 1384; mild: n = 69; moderate: n = 3580; severe: n = 1176).
Complete carotid ultrasound data were available for 5781 partici-
pants of this sample (Figure 1).
3.1.2  |  Socio-­demographic characteristics
Socio-­demographic characteristics differed significantly (p  < .001)
according to CP severity (Table  1). The proportion of women was
higher among participants with none CP (60.8%) as compared with
the other groups (mild: 52.2%, moderate: 50.7%; severe: 39.1%).
Participants with severe CP were of older age (Median [IQR]: 66 [59,
71]) and presented the highest rates for BMI (26.45 [24.11, 29.65])
and lower educational level (4.1%) in comparison to none, mild and
moderate CP.
3.1.3  |  Cardiovascular risk factors
Moreover, cardiovascular risk factors differed significantly by CP
severity (Table  1). Participants with severe CP had the highest
percentage of smokers (n  =  293; 25.1%), being diabetic (n  = 122;
11.3%) and hypertensive (n = 810; 72.5%), all statistically significant
(p  < .001). Regarding previous vascular events, again participants
LAMPRECHT et al.       5|
TA B L E 1  Characteristics of the study population stratified by periodontitis grades

Periodontitis

None Mild Moderate Severe

n 1384 69 3580 1176 p

Sex = Female (%) 842 (60.8) 36 (52.2) 1814 (50.7) 460 (39.1) <.001
Age (median [IQR]) 59.00 [52.00, 59.00 [53.00, 66.00] 63.00 [55.00, 69.00] 66.00 [59.00, 71.00] <.001
66.00]
Education (%)
Low 40 (3.0) 3 (4.5) 151 (4.4) 55 (5.0) .003
Medium 642 (48.4) 33 (50.0) 1711 (50.0) 605 (54.5)
High 645 (48.6) 30 (45.5) 1559 (45.6) 450 (40.5)
BMI (median [IQR]) 25.55 [22.98, 25.73 [23.49, 29.33] 26.02 [23.55, 29.01] 26.45 [24.11, 29.65] <.001
28.60]
Current Smoking (%) 215 (15.6) 20 (29.4) 608 (17.1) 293 (25.1) <.001
Diabetes (%) 82 (6.2) 3 (4.5) 242 (7.4) 122 (11.3) <.001
Hypertension (%) 728 (54.5) 40 (62.5) 2266 (66.3) 810 (72.5) <.001
Sys. blood pressure 134.00 [123.50, 133.00 [123.12, 144.38] 137.50 [125.50, 150.50] 139.50 [127.50, 153.00] <.001
(median [IQR]) 146.50]
Dia. blood pressure 81.50 [75.00, 79.50 [74.75, 86.38] 82.00 [76.00, 88.50] 81.50 [75.50, 88.50] .046
(median [IQR]) 87.25]
Heart rate (median [IQR]) 67.50 [61.00, 75.00] 67.75 [61.38, 71.62] 68.50 [62.00, 76.00] 68.50 [61.50, 76.50] .020
Heart failure (%) 22 (1.6) 1 (1.4) 76 (2.1) 31 (2.7) .308
Atrial fibrillation (%) 53 (4.2) 4 (6.0) 181 (5.5) 75 (6.9) .040
Myocardial infarction (%) 30 (2.2) 1 (1.4) 88 (2.5) 38 (3.3) .310
Stroke (%) 24 (1.7) 3 (4.3) 98 (2.8) 45 (3.9) .011
Stenosis ACI right (%) 0 (0.0) 0 (0.0) 12 (0.4) 7 (0.6) .051
ACI flow velocity stenosis NA NA 1.25 [0.66, 2.02] 1.41 [0.78, 1.85] .920
right (median [IQR])
Stenosis ACI left (%) 2 (0.2) 0 (0.0) 9 (0.3) 4 (0.4) .757
ACI flow velocity stenosis 1.84 [1.34, 2.35] NA [NA, NA] 1.32 [0.91, 2.33] 1.70 [1.17, 2.22] .904
left (median [IQR])
Carotis plaque (%) 311 (23.8) 17 (26.2) 993 (29.0) 451 (40.2) <.001
Carotis plaque diameter 2.11 [1.78, 2.54] 2.40 [2.09, 2.86] 2.18 [1.81, 2.60] 2.17 [1.81, 2.66] .061
(median [IQR])
cIMT ≥1 mm (%) 62 (4.7) 8 (12.5) 208 (6.1) 113 (10.0) <.001
cIMT (median [IQR]) 0.72 [0.64, 0.81] 0.73 [0.68, 0.86] 0.75 [0.67, 0.84] 0.78 [0.69, 0.88] <.001
eGFR (median [IQR]) 87.30 [76.80, 95.85] 89.25 [81.50, 95.90] 86.20 [75.50, 94.20] 84.70 [73.93, 92.50] <.001
hsCRP (median [IQR]) 0.10 [0.06, 0.22] 0.13 [0.06, 0.34] 0.11 [0.06, 0.25] 0.13 [0.07, 0.30] <.001
LDL (median [IQR]) 117.00 [96.00, 123.50 [84.00, 150.50] 122.00 [97.00, 145.00] 121.00 [93.75, 146.00] .294
145.00]
Non-­HDL-­cholesterol 140.00 [115.00, 146.00 [105.75, 176.50] 143.00 [117.00, 171.00] 144.00 [114.00, 171.00] .332
(median [IQR]) 169.00]
Anticoagulant 140 (10.4) 6 (9.0) 466 (13.7) 187 (16.8) <.001
medication (%)
Antihypertensive 348 (25.7) 23 (34.3) 1109 (32.5) 410 (36.8) <.001
medication (%)
Statins (%) 166 (12.3) 8 (11.9) 501 (14.7) 218 (19.6) <.001
Antidiabetic 55 (4.1) 2 (3.0) 161 (4.7) 86 (7.7) <.001
medication (%)

(Continues)
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6      LAMPRECHT et al.

TA B L E 1  (Continued)

Periodontitis

None Mild Moderate Severe

n 1384 69 3580 1176 p

Number of missing teeth 2.00 [0.00, 4.00] 2.00 [0.00, 6.00] 2.00 [1.00, 5.00] 4.00 [1.00, 9.00] <.001
(median [IQR])
DMFT-­Index (median 17.00 [14.00, 21.00] 18.00 [15.00, 22.00] 19.00 [16.00, 23.00] 21.00 [17.00, 24.25] <.001
[IQR])
AL sites ≥3 mm (median 12.35 [6.39, 20.71] 14.88 [9.03, 22.84] 38.67 [25.64, 53.61] 68.52 [53.21, 83.33] <.001
[IQR])
BOP (median [IQR]) 2.08 [0.00, 7.14] 2.92 [0.00, 6.90] 8.33 [2.17, 19.23] 21.05 [9.26, 41.67] <.001
Plaque index (median 0.00 [0.00, 10.93] 0.00 [0.00, 8.93] 8.93 [0.00, 27.78] 22.00 [5.77, 54.76] <.001
[IQR])
Antibiotic use within last 161 (11.8) 3 (4.3) 399 (11.2) 116 (9.9) .141
three months (%)

Abbreviations: ACI, arteria carotis interna; AL, attachment loss; BMI, body mass index; BOP, bleeding on probing; cIMT, carotid intima-­media
thickness; DMFT, decayed; missing and filled teeth; eGFR, estimated glomerular filtration rate; HDL, high-­density lipoprotein; hsCRP, high-­sensitivity
C-­reactive protein; IQR, interquartile range; LDL, low-­density lipoprotein.

TA B L E 2  Periodontal status related to

Age decades
age decades
45–­54 55–­6 4 65+

n = 2273 n = 3322 n = 4405

Median [IQR] or n (%) p-­value

Periodontitis
None or mild (%) 505 (34.6) 494 (23.2) 454 (17.3) <.001
Moderate (%) 795 (54.6) 1260 (59.2) 1525 (58.1)
Severe (%) 158 (10.8) 372 (17.5) 646 (24.6)
Number of missing teeth [IQR] 1 [0, 3] 2 [1, 6] 4 [1, 9] <.001
DMFT-­Index [IQR] 16 [13, 20] 19 [16, 23] 22 [18, 25] <.001
Sites/mouth CAL ≥3 mm [IQR] 28.82 36.31 [19.14, 42.26 [23.68, <.001
[14.78, 56.06] 62.82]
47.55]
BOP [IQR] 6.25 [1.85, 7.89 [1.92, 8.93 [2.08, <.001
17.35] 20.83] 21.43]
Plaque index [IQR] 5.56 [0, 7.41 [0, 12 [0, 36.54] <.001
22.73] 27.27]

Abbreviations: BOP, bleeding on probing; CAL, clinical attachment loss; DMFT, decayed; missing
and filled teeth; IQR, interquartile range.

with severe CP were of highest rates for stroke (3.9%, p = 0.008),
but with no significant difference for heart failure (2.7%; p = 0.166)
and myocardial infarction (3.3%; p = 0.18). Additionally, medication
with statins, anti-­hypertensives, and anti-­diabetics was common in
this sample and differed significantly according to the periodontal
status (p  < .001, Table  1) between groups, with the highest per-
centage of treated participants was observed in subjects with se-
vere CP. Regarding blood biomarker values (Table  1), participants
with severe CP showed the highest for hsCRP (0.13 [0.07, 0.3],
p  =  0.013). Values for LDL-­ and Non-­HDL-­cholesterol were of no
statistical difference.
3.1.4  |  Carotid intima-­media thickness
The median of cIMT and the prevalence of cIMT ≥ 1 mm were sig-
nificantly higher in men and women with CP in bivariate analysis
(p  < .001, Table  1). Moderate and severe CP were both associated
with higher median cIMT (median [IQR]: severe: 0.78 [0.7, 0.88];
moderate: 0.75 [0.67, 0.84]; mild: 0.73 mm [0.68, 0.86]); none:
0.72 mm [0.64–­0.81], and cIMT ≥1 mm (severe: 10%; moderate: 6.1%;
mild: 12.5%; none: 4.7%) compared to none or mild CP. Additionally,
the two groups both showed a higher percentage of occurrence of
plaques (severe: 40.2%; moderate: 29%; mild: 26.2%; none: 23.8%).
LAMPRECHT et al.
3.1.5  |  Dental parameters
Severe CP was associated with higher rates of CAL (mean: 68.52%),
BOP (Median [IQR]: 21.05 [9.26, 41.67]) and plaque index (22 [5.77,
54.76]) in comparison to none, mild and moderate CP. Dental pa-
rameters differed significantly with age decades (p < .001, Table 2).
About half of the participants of all three age decades (years:
45–­54; 55–­6 4; 65+) had moderate CP. Nearly a quarter of partic-
ipants aged ≥65 years (n  =  646; 24.6%) had severe CP (55–­6 4ys:
n  =  372; 17.5%; 45–­54ys: n  =  158; 10.8%). In contrast, more than
a third (n = 505; 34.6%) of participants aged 45–­54 years had none
or mild CP. Furthermore, a higher age decade was associated with
higher values of number of missing teeth, DMFT, CAL, BOP, and PI.
Accordingly, the highest rates of these parameters were measured in
participants aged ≥65 (Table 2).
3.2  |  Multiple linear regression analyses
The multiple linear regression analyses with complete case models
were performed on 5781 (bivariate model) and 5407 (Table 3–­model
2–­5) participants. Severe CP was significantly associated with cIMT in
all five models (p < .001). The β-­coefficients for severe and for moder-
ate CP decreased with the number of added confounders [severe CP:
bivariate: 0.066; model 2 (age, sex, smoking, diabetes): 0.021; model 3
(age, sex, smoking, diabetes, hypertension): 0.017; model 4 (age, sex,
smoking, diabetes, log hsCRP): 0.02; model 5 (age, sex, diabetes, hy-
pertension, education, hypercholesterolemia): 0.023. Moderate CP:
bivariate: 0.033; model 1: 0.01; model 2: 0.007; model 3: 0.01; model
4: 0.008]. However, they remained significant in all models except for
moderate CP in models 1 and 4 adjusted for hypertension.
3.3  |  Multiple logistic regression analyses
The unadjusted logistic regression model showed that both, moder-
ate and severe CP, were strongly associated with the presence of
carotid plaque and/or cIMT ≥1 mm (OR: 1.36 [95% CI: 1.18–­1.57;
p  < .001] for moderate and 2.27 [95% CI: 1.91–­2.70; p  < .001] for
severe CP. Adjusting for age and sex attenuated the association,
which remained significant for severe CP (OR: 1.38; p  = .001) but
not for moderate CP (OR: 1.01; p = 0.893) (Table 4). Further adjust-
ments for smoking, diabetes, hypertension, and hsCRP, which were
all associated with carotid plaque/cIMT ≥ 1 mm, had only a small ad-
ditional attenuating effect on the association (decrease of the ORs
from 1.38 (95% CI: 1.14–­1.66, p = .001) to 1.31 (95% CI: 1.08–­1.61,
p = .008) (Table 4).
4  |   D I S C U S S I O N
To date, this is one of the largest studies investigating the asso-
ciation between the periodontal status and carotid atherosclerosis
|
      7
in a population-­based sample of men and women between 45
and 74 years. Moderate and severe CP were both associated with
higher median cIMT and a higher prevalence of carotid plaque and
cIMT ≥ 1 mm compared to none or mild CP. After adjusting for sev-
eral confounders (age, sex, diabetes, smoking, education, hypercho-
lesterolemia, and CRP) in linear regression analyses, moderate and
severe CP were associated with cIMT. After additional adjustment
for hypertension, the association with cIMT remained significant for
severe CP, whereas the significance threshold was narrowly missed
for moderate CP. After adjusting for hypertension, a notable reduc-
tion of the resulting β-­coefficient was observed. In contrast, adjust-
ments for hsCRP, education, and hypercholesterolemia had hardly
any effect on the resulting β-­coefficients.
The observed bivariate associations are consistent with previous
studies.38,39 Cross-­sectional data on 6017 persons aged 52–­75 years
from the Atherosclerosis Risk in Communities (ARIC) Study.11 In the
ARIC study, the odds of cIMT ≥1 mm was higher for severe CP (odds
ratio (OR) 2.09) and moderate CP (OR 1.40) compared to none or
mild periodontitis. Multivariable logistic regression analyses showed
that severe CP was associated with cIMT ≥1 mm, after adjusting
for covariates age, sex, diabetes, LDL-­ and HDL-­cholesterol, tri-
glycerides, hypertension, smoking, waist-­hip ratio, education, and
race/study center (OR 1.31, 95% CI 1.03–­1.66).
Yu et al. 25 observed a linear and dose-­dependent association
between periodontal measures including mean CAL and maximal
cIMT and carotid plaque load in elderly hyperglycemic subjects from
China, which could, however, not be detected in euglycemic sub-
jects. The study was considerably smaller than ARIC or our present
study, suggesting that it may have been underpowered to detect the
association in euglycemic subjects. Bell et al. 26 used Mendelian ran-
domization to test whether CP is causally associated with increased
cIMT. They found no correlation for CP and subclinical atheroscle-
rosis, suggesting that the associations observed in observational
studies may represent confounding. However, it must be noted that
the Mendelian randomization approach may not be valid in this spe-
cial case because the single nucleotide polymorphisms that were
employed in the study explained only a very small fraction of the
occurrence of CP in the population. This fact may have masked the
association. According to Leite et al. 24 the association between CP
and cIMT could be due to a collider bias, which can produce an as-
sociation where there is no true causal effect in the general popu-
lation. The argument relates to their finding that stratified analyses
according to the hsCRP level revealed that the magnitude of the
association was higher among participants with hsCRP ≥3  mg/L,
with 36% collider bias probability, whereas no association between
CP and cIMT was found among participants with hsCRP < 3  mg/L.
Although we did not stratify our study sample according to hsCRP
level, the fact that we observed virtually no effect on the result-
ing β-­coefficients after adjusting the regression models for hsCRP,
strongly argues against this kind of bias. According to a hypothesis,
which was first formulated by Hujoel and coworkers in 2002,40 an
inadequate control for smoking, such as underreporting in epide-
miological surveys, may produce an association with the explored
 |
8      LAMPRECHT et al.

TA B L E 3  Linear regression analysis of associations between the TA B L E 3  (Continued)

periodontal status and cIMT
Parameter β (95% CI) p-­value
Parameter β (95% CI) p-­value
Diabetes 0.026 (0.012, 0.040) <.001
Model 1 (age, sex, smoking, diabetes) Education (medium) −0.023 (−0.042, −0.004) .018
Age 0.007 (0.006, 0.007) <.001 Education (high) −0.026 (−0.045, −0.007) .008
Sex Hypertension 0.028 (0.020, 0.036) <.001
Male Reference Hypercholesterolemia 0.005 (−0.003, 0.013) .220
Female −0.039 (−0.046, −0.031) <.001
Abbreviations: hsCRP, high-­sensitivity C-­reactive protein.
Smoking 0.022 (0.012,0.031) <.001
Diabetes 0.030 (0.016,0.043) <.001
systemic condition artificially. Clearly, we cannot completely dismiss
Periodontitis
the possibility of residual confounding, which may have been due to
None or mild Reference
miss-­classification and/or other issues. Therefore, the results must
Moderate 0.01 (0.001, 0.019) .017 be interpreted cautiously.
Severe 0.021 (0.009, 0.032) <.001 Due to the cross-­sectional design of the previous and current
Model 2 (age, sex, smoking, diabetes, hypertension) studies, no formal causal relationship between CP and carotid ath-
Age 0.006 (0.006, 0.007) <.001 erosclerosis can be proven. Clinical and in-­vitro studies are available
Sex whereby periodontal therapy may improve endothelial function
Male Reference and reduces biomarkers of atherosclerotic vascular disease are
Female −0.035 (−0.042, −0.027) <.001 available.15,40,41 Moreover, one study showed that nonsurgical peri-

Periodontitis
odontal treatment had a positive effect on cIMT.42 Furthermore,
other studies stated that inflammatory changes in the gingiva can
None or mild Reference
lead to a systemic increase of inflammatory markers and endothelial
Moderate 0.007 (−0.001, 0.016) .1
dysfunction,14 which can support the development of atheroscle-
Severe 0.017 (0.006, 0.029) <.001
rosis and an increase of cIMT.13 In our study, CRP and the odds of
Diabetes 0.026 (0.012, 0.039) <.001
cIMT ≥1 mm increased as a function of CP severity grades in non-­
Smoking 0.022 (0.012, 0.031) <.001
adjusted analysis. Thus, our data do not exclude that inflammation
Hypertension 0.029 (0.021, 0.037) <.001 plays a role in the mechanism of cIMT elevation. The statistical
Model 3 (age, sex, smoking, diabetes, log hsCRP) models show that CRP was not associated with cIMT ≥ 1 mm after
Age 0.007 (0.006, 0.007) <.001 adjusting for age and sex, whereas aging and male sex are strongly
Sex associated with increased cIMT. It is known that the plasma con-
Male Reference centration of CRP is higher in healthy individuals aged over 65 years
Female −0.039 (−0.046, −0.031) <.001 compared to younger people 43 and that healthy women have higher

Periodontitis CRP levels than healthy men.44 On the other hand, aging and sex
are linked to a vast number of additional effects. Therefore, an in-
None or mild Reference
vestigation of the causal relationship between poor oral health and
Moderate 0.01 (0.001, 0.019) .022
increased cIMT is beyond the scope of the study.
Severe 0.02 (0.008, 0.031) .001
A unique feature of the present study is the comprehensive den-
Diabetes 0.026 (0.012, 0.039) <.001
tal examination, which is in line with multinational efforts to pro-
Smoking 0.018 (0.009, 0.028) <.001
vide standards for reporting of CP prevalence and severity.46 The
Log hsCRP 0.01 (0.006,0.013) <.001 full-­mouth examination enabled application of the internationally
Model 4 (age, sex, diabetes, hypertension, education, and accepted CDC-­A AP criteria for correctly staging CP according to its
hypercholesterolemia)
severity33 and also included determinations of the DMFT, BOP and
Age 0.006 (0.005, 0.006) <.001 plaque indices to characterize oral health more broadly than usual.
Sex Recently, a new case definition was introduced for classification of
Male Reference CP47; however, since the study design of our study preceded its in-
Female −0.033 (−0.041, −0.026) <.001 troduction, this definition was not used here. An advantage of the
Periodontitis use of the old CDC-­A AP classification was that it has been widely
None or mild Reference used in epidemiological studies, whereas the new periodontitis
Moderate 0.008 (−0.001, 0.016) .099 classification has so far been rarely used in epidemiological stud-

Severe 0.023 (0.011, 0.034) <.001 ies. Therefore, comparisons of our current results with previously
published results were more straightforward than under the new
classification.
LAMPRECHT et al. |
      9

TA B L E 4  Logistic regression analysis of associations between

the periodontal status and cIMT ≥1 mm and/or presence of carotid
5  |  CO N C LU S I O N
plaque
In this recently recruited study, severe CP was associated with
Odds
increased cIMT and higher prevalence of carotid plaques after
ratio 95% CI p-­value
adjustment for common risk factors, including age, sex, smoking,
Model 1 —­Exposure: periodontitis; outcome: plaque = yes and/or
diabetes, hypertension, education, hypercholesterolemia, and
IMT ≥1 mm. Adjustments: age, sex
CRP.
Periodontitis = moderate 1.01 0.87–­1.18 .893
Periodontitis = severe 1.38 1.14–­1.66 .001
AU T H O R C O N T R I B U T I O N S
Age 1.10 1.10–­1.11 <.001 Lamprecht, R: Contributed to acquisition, drafted and critically
Sex = Female 0.61 0.54–­0.69 <.001 revised the manuscript; Rimmele DL: Contributed to acquisi-
Model 2 —­Exposure: periodontitis; outcome: plaque = yes and/ tion, drafted and critically revised the manuscript; Schnabel, RB:
or IMT ≥1 mm. Adjustments: age, sex, smoking, diabetes,
Contributed to acquisition and analysis, and critically revised the
hypertension, hsCRP
manuscript; Heydecke, G: Contributed to interpretation and criti-
Periodontitis = moderate 0.99 0.84–­1.17 .902
cally revised the manuscript; Seedorf U: Contributed to concep-
Periodontitis = severe 1.31 1.08–­1.61 .008
tion and design, analysis and interpretation, and critically revised
Age 1.10 1.09–­1.11 <.001 the manuscript; Walther, C: Contributed to interpretation, drafted
Sex = Female 0.65 0.57–­0.73 <.001 and critically revised the manuscript; Mayer C: Contributed to
Smoking 1.74 1.47–­2.06 <.001 interpretation, drafted and critically revised the manuscript;
Diabetes 1.28 1.02–­1.61 .036 Struppek, J: Contributed to acquisition and interpretation and
Hypertension 1.67 1.44–­1.94 <.001 critically revised the manuscript; Borof, K: Contributed to design
log hsCRP 1.09 1.02–­1.17 .007 and interpretation, performed all statistical analyses, drafted and
critically revised the manuscript; Behrendt CA: Contributed to
Abbreviations: hsCRP, high sensitivity C-­reactive protein; Reference,
no/mild periodontitis. acquisition and analysis, and critically revised the manuscript;
Cheng B: Contributed to acquisition and analysis, and critically
revised the manuscript; Gerloff C: Contributed to interpreta-
Although our observations are in general agreement with the tion and critically revised the manuscript; Debus S: Contributed
findings of the ARIC study,11 some notable differences were ob- to interpretation and critically revised the manuscript; Smeets,
served. In our present study, despite a similar age-­ and sex distri- R: Contributed to conception and design, and critically revised
bution, the prevalence of cIMT ≥1 mm as well as the prevalence manuscript; Beikler, T: Contributed to interpretation and criti-
of severe CP was lower. Although the reasons for these differ- cally revised the manuscript; Blankenberg, S: Contributed to
ences are not entirely clear, it is important to note that the ARIC conception and design, and critically revised manuscript; Zeller
results were obtained 20 years ago, and the measurements were T: Blankenberg, S: Contributed to acquisition and analysis, and
conducted as early as 1996. According to data from the NCH Risk critically revised manuscript; Karakas, M: Contributed to in-
Factor Collaboration, the age-­adjusted incidence rates of CVD terpretation and critically revised the manuscript; Thomalla T:
endpoints and the prevalence of risk factors have been decreasing Contributed to conception and design, and critically revised man-
over the past 20 years, most likely partly due to beneficial lifestyle uscript; Aarabi G: Contributed to conception and design, analysis
27,28
changes and improvements of medicine. The same applies to and interpretation, and critically revised the manuscript. All au-
the age-­adjusted incidence rates of CP and the prevalence of the thors gave their final approval and agree to be accountable for all
corresponding risk factors, which also follow declining trends in aspects of the work.
Germany. 29 Due to these secular and longitudinal trends, the general
state of health of our study sample may have been better compared AC K N OW L E D G E M E N T
to the ARIC study. A plausible reason may relate to more widespread Open Access funding enabled and organized by Projekt DEAL.
current drug treatment of CVD risk factors, such as hypercholester-
olemia, hypertension and diabetes. Such drug use was very common C O N FL I C T S O F I N T E R E S T
in our sample. Statins, which are used to treat hypercholesterolemia, No conflicts of interests.
and metformin, which is an anti-­diabetic drug, may have beneficial
effects not only on the CVD risk factors, but also on CP.47,48 This DATA AVA I L A B I L I T Y S TAT E M E N T
might have affected the observations. On the other hand, the gen- The data that support the findings of this study are available from the
eral finding of an association between CP and increased cIMT / Hamburg City Health Study (HCHS). Restrictions apply to the avail-
carotid plaque, which is independent from a set of important con- ability of these data, which were used under license for this study.
founding variables, remains the same. Data are available from the authors with the permission of HCHS.
 |
10      LAMPRECHT et al.
ORCID
Carolin Walther  https://orcid.org/0000-0002-1307-5672
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