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JDRXXX10.1177/0022034518814829Journal of Dental ResearchTooth Loss Predicts MI, Heart Failure, Stroke, and Death

Research Reports: Clinical

Journal of Dental Research
2019, Vol. 98(2) 164­–170
Tooth Loss Predicts Myocardial Infarction, © International & American Associations
for Dental Research 2018

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DOI: 10.1177/0022034518814829
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H.J. Lee1, E.K. Choi1 , J.B. Park2, K.D. Han3, and S. Oh1

Abstract
We investigated whether oral health, represented by missing teeth, was associated with an increased risk of cardiovascular disease,
including myocardial infarction (MI), heart failure (HF), stroke, and all-cause mortality. Subjects who underwent routine dental
examinations and health checkups provided by the Korean National Health Insurance from 2007 to 2008 (n = 4,440,970) were followed
up for incident MI, HF, stroke, and death until 2016. During follow-up of 7.56 y, 68,063 (1.5%) subjects died, and 31,868 (0.7%) were
admitted for MI, 22,637 (0.5%) for HF, and 30,941 (0.7%) for stroke. Cardiovascular events and mortality increased in proportion to
tooth loss. Tooth loss was an independent risk factor for cardiovascular events after multivariable analysis adjusted for cardiovascular
risk, behavioral, and income factors. Each missing tooth was associated with an approximately 1% increase in MI (HR, 1.010; 95% CI,
1.007 to 1.014), 1.5% increase in HF (HR, 1.016; 95% CI, 1.013 to 1.019) and stroke (HR, 1.015; 95% CI, 1.012 to 1.018), and 2% increase
in mortality (HR, 1.022; 95% CI, 1.020 to 1.023). Having ≥5 missing teeth substantially increased risk for cardiovascular outcomes, and
even a small number of missing teeth (1 to 4) was associated with an increased risk for MI, stroke, and death. This association was
consistent in subgroup analyses and especially strong among the younger subjects (age <65 y) and those with periodontitis. In this
large Korean nationwide cohort study, we found that tooth loss showed a dose-dependent association with incident MI, HF, ischemic
stroke, and all-cause death and was a good predictor of cardiovascular outcome. In clinical practice, the number of missing teeth can aid
physicians in discriminating patients with a higher cardiovascular risk.

Keywords: cardiovascular diseases, dental caries, periodontitis, mortality, epidemiology, risk factors

Introduction failure (HF), and all-cause mortality, adjusting for possible

Oral diseases such as periodontitis and caries are very com-
mon, and prevalence increases with age. Epidemiologic stud-
ies have shown that in Korea the prevalence of significant
periodontitis is 25% to 30% (Lee et al. 2015; Hong et al. 2016)
and the prevalence of dental caries is 80% to 90% (Lee et al.
2012), values that are similar worldwide (Zhang et al. 2014;
Eke et al. 2015). Caries and periodontal disease are the main
reasons for tooth loss, with the latter becoming predominant
from middle age on. A substantial body of evidence supports
that poor oral health is associated with subclinical atheroscle-
rosis and cardiovascular disease (CVD; Desvarieux et al. 2003;
Lockhart et al. 2012), although causality is yet unclear. Oral
disease and CVD share common risk factors, such as age, male
sex, smoking, diabetes, hypertension, and obesity, which may
act as confounding factors. However, the link between oral dis-
ease and CVD may be explained by chronic inflammation and
repeated bacteremia from the oral cavity, as inflammation
plays an important role in the pathogenesis of atherosclerosis.
Tooth loss is a simple and objective proxy for the accumulated
inflammatory burden of oral disease and was independently
associated with cardiovascular events and mortality in previ-
ous epidemiologic studies (Tu et al. 2007; Liljestrand et al.
2015; Joshy et al. 2016).
We aimed to assess the association between oral health rep-
resented by tooth loss and long-term cardiovascular outcomes,
including myocardial infarction (MI), ischemic stroke, heart
confounding factors in a nationwide population-based cohort.
To our knowledge, this is the largest study to investigate the
association between tooth loss and each cardiovascular out-
come in a single cohort.
Methods
Study Population and Data Collection
The study population was recruited from the database of the
National Health Insurance Service (NHIS), which provides
health care benefits and regular health checkups for the total
Korean population and can be used for population-based
studies. Details of the data source and health examinations are
1
Division of Cardiology, Department of Internal Medicine, Seoul
National University Hospital, Seoul, Republic of Korea
2
Department of Periodontics, College of Medicine, The Catholic
University of Korea, Seoul, Republic of Korea
3
Department of Biostatistics, College of Medicine, The Catholic
University of Korea, Seoul, Republic of Korea
A supplemental appendix to this article is available online.
Corresponding Author:
E.K. Choi, Division of Cardiology, Department of Internal Medicine,
Seoul National University Hospital, 101 Daehak-ro, Jongno-gu, Seoul
03080, Republic of Korea.
Email: choiek17@snu.ac.kr
Tooth Loss Predicts MI, Heart Failure, Stroke, and Death
available in the Appendix. From the NHIS database, we
extracted 6,077,073 dental examination results of Korean
adults (≥20 y old) from the regular health checkups done in
2007 to 2008: 1,250,876 subjects did not undergo the rest of
the health examinations and were excluded; 240,477 under-
went dental examinations both years, and the results from 2007
were used. This resulted in 4,585,720 subjects who underwent
dental examinations in 2007 to 2008.
From this initial population, we excluded 180,750 subjects
with prior diagnoses of MI, HF, or stroke from 2002 (when
data collection was initiated) to the initial health checkup to 1)
wash out diagnosis claims representing prior events and 2)
detect new-onset MI, HF, or stroke for clinical endpoints. This
secured adequate washout periods of at least 5 y for previous
diagnoses. Therefore, 4,440,970 subjects were finally included
in the cohort (Appendix Fig. 1). This cohort was followed up
until 2016.
Standardized health examinations were performed in hospi-
tals certified by the NHIS. Dental examinations included
inspection by a dentist, questionnaires for dental hygiene, and
oral health instructions. Results included number of teeth lost
and presence of periodontal disease. We defined the maximum
number of teeth as 28, excluding the third molars from the
count. Groups were divided according to number of tooth loss
(0, 1 to 4, 5 to 14, 15 to 27, 28). The group with a tooth loss of
28 represented edentulous individuals; to note, as the third
molars were not counted, this category may include subjects
with remaining third molars. This study was conducted accord-
ing to the Declaration of Helsinki and was approved by the
Institutional Review Board of Seoul National University
Hospital (E-1803-098-931).
Definition of Endpoint and Other Variables
The 10th revision of the International Statistical Classification
of Diseases and Related Health Problems (ICD-10) was
applied for the classification of the diseases. The cardiovascu-
lar endpoints were de novo occurrence of MI (ICD-10 codes
I21 and I22), HF (ICD-10 code I50), ischemic stroke (ICD-10
codes I63 and I64), and all-cause death during the follow-up
period. The outcomes were followed up independently, and the
first incidence of each outcome was counted. The definitions
of cardiovascular outcomes and comorbidities were defined
with ICD-10 codes with additional information. They are sum-
marized in Appendix Table 1 and were described in our previ-
ous reports (Lee et al. 2017; Park et al. 2018).
Statistical Analysis
Data are presented as numbers and percentages for categorical
variables and as means with standard deviation for continuous
variables. The chi-square test was used to compare categorical
variables, and analysis of variance was used to compare con-
tinuous variables. The annual event incidence rates were calcu-
lated as the number of events per 1,000 person-years. Cox
proportional hazard models were used to estimate the hazard
ratios (HRs) and the corresponding 95% CIs for the association
165
between tooth loss and cardiovascular endpoints. The propor-
tional hazards assumption was evaluated graphically by the
analyst with “log-log” plots. Time was defined as days from
inclusion to either cardiovascular outcome or censoring due to
emigration or end of follow-up. Multivariable adjustment was
done for age, sex, body mass index (BMI), diagnosis of diabe-
tes mellitus, hypertension, dyslipidemia, chronic obstructive
pulmonary disease (COPD), end-stage renal disease, smoking
history, drinking history, exercise habits, and low income level.
Subgroup analyses for cardiovascular risk associated with
increasing tooth loss according to age, sex, obesity, comorbidi-
ties, lifestyle habits, income, and presence of periodontitis
were performed. Further analyses of interaction on an additive
scale were performed for variables showing significant inter-
action on a multiplicative scale. Two-sided P values <0.05
were considered statistically significant. Statistical tests were
performed with SAS 9.3 (SAS Institute) and Stata 12
(StataCorp).
Results
Baseline Characteristics of Study Population
The study cohort consisted of 4,404,970 subjects with a median
follow-up of 7.59 y (SD, 0.72 y). The baseline characteristics
of the study population are presented in Table 1. In brief, the
mean age of the total population at baseline was 41.5 y; 61.6%
were male; 97.8% had <5 missing teeth; and 2.2% had ≥5
missing teeth. The groups with a higher number of tooth loss
were older, had a higher prevalence of chronic diseases, and a
higher proportion of low income.
Independent Predictive Value of Tooth Loss
for Cardiovascular Events
A total of 68,063 (1.5%) subjects died during follow-up.
Among those who survived, 31,868 (0.7%) experienced MI;
22,637 (0.5%), HF; and 30,941 (0.7%), stroke. The overall
incidence rates of MI, HF, stroke, and all-cause death among
the total population were 0.95, 0.67, 0.92, and 2.01 per 1,000
person-years, respectively.
Incidence rates of cardiovascular events according to num-
ber of teeth lost are shown in Figure 1. Incidence rates for MI,
HF, stroke, and death increased almost linearly in proportion to
the number of tooth loss. Risk for MI, HF, stroke, and death,
represented by adjusted HR with 95% CI, also increased with
higher levels of tooth loss (Appendix Fig. 2). Tooth loss was an
independent risk factor for cardiovascular events after multi-
variable analysis (Table 2). A graded and independent risk was
observed between tooth loss and all cardiovascular outcomes,
and subjects with ≥15 missing teeth had the highest risk. This
association tended to be stronger with the greater the number
of teeth lost, and it persisted after comprehensive adjustment
for other cardiovascular risk factors. Having ≥5 missing
teeth substantially increased the risk for all cardiovascular out-
comes, and even a small number of missing teeth (1 to 4) was
associated with an increased risk for MI, stroke, and death. To
166 Journal of Dental Research 98(2)

Table 1. Baseline Characteristics of the Study Population.

No. of Missing Teeth

0 (n = 3,978,654) 1 to 4 (n = 329,461) 5 to 14 (n = 81,337) 15 to 27 (n = 12,601) 28 (n = 2,917) P Value

a
Age, y 40.7 ± 12.2 46.7 ± 12.3 55.1 ± 11.5 68.9 ± 10.0 68.6 ± 9.7 <0.0001
Male 2,436,976 (61.3) 215,536 (65.4) 50,822 (62.5) 7,128 (56.6) 1,424 (42.8) <0.0001
Body mass index, kg/m2 <0.0001
<18.5 175,864 (4.4) 9,697 (2.9) 2,345 (2.9) 653 (5.2) 177 (6.1)
18.5 to 22.9 1,651,412 (41.5) 120,794 (36.7) 28,567 (35.1) 5,051 (40.1) 1,267 (43.4)
23 to 24.9 968,538 (24.3) 84,566 (25.7) 21,018 (25.8) 3,044 (24.2) 647 (22.2)
25 to 29.9 1,066,099 (26.8) 102,932 (31.2) 26,292 (32.3) 3,486 (27.7) 742 (25.4)
≥30 116,741 (2.9) 11,472 (3.5) 3,115 (3.8) 367 (2.9) 84 (2.9)
Periodontitis 1,929,799 (48.5) 191,180 (58.0) 49,680 (61.1) 5,270 (41.8) 74 (2.5) <0.0001
Past medical history
Diabetes mellitus 185,775 (4.7) 28,694 (8.7) 11,677 (14.4) 2,268 (18.0) 520 (17.8) <0.0001
Hypertension 653,660 (16.4) 82,649 (25.1) 30,149 (37.1) 6,026 (47.8) 1,491 (51.1) <0.0001
Dyslipidemia 441,223 (11.1) 47,408 (14.4) 14,542 (17.9) 2,561 (20.3) 645 (22.1) <0.0001
COPD 335,475 (8.4) 32,054 (9.7) 10,586 (13.01) 2,490 (19.8) 707 (24.2) <0.0001
End-stage renal disease 621 (0.02) 80 (0.02) 35 (0.04) 8 (0.06) 1 (0.03) <0.0001
Smoking <0.0001
Never smoker 2,448,221 (61.5) 180,365 (54.8) 47,055 (57.9) 8,109 (64.4) 1,981 (67.9)
Ex-smoker 42,0178 (10.6) 37,493 (11.4) 7,995 (9.8) 1,159 (9.2) 267 (9.2)
Current smoker 1,110,255 (27.9) 111,603 (33.9) 26,287 (32.3) 3,333 (26.5) 669 (22.9)
Drinking <0.0001
Never 1,709,369 (43.0) 145,127 (44.1) 42,896 (52.7) 8,220 (65.2) 2,102 (72.1)
<1/wk 1,967,712 (49.5) 149,038 (45.2) 28,084 (34.5) 2,837 (22.5) 525 (18.0)
≥1/wk 301,573 (7.6) 35,296 (10.7) 10,357 (12.7) 1,544 (12.3) 290 (9.9)
Exercise <0.0001
None 1,930,744 (48.5) 156,667 (47.6) 41,479 (51.0) 7,305 (58.0) 1,919 (65.8)
<3 times/wk 1,798,391 (45.2) 148,031 (44.9) 31,709 (39.0) 3,595 (28.5) 639 (21.9)
≥3 times/wk 249,519 (6.3) 24,763 (7.5) 8,149 (10.0) 1,701 (13.5) 359 (12.3)
Lowest-income quartile 675,144 (17.0) 72,611 (22.0) 22,116 (27.2) 3,295 (26.2) 703 (24.1) <0.0001

COPD, chronic obstructive pulmonary disease.

a
Mean ± SD.

Subgroup Analyses of Cardiovascular Risk

No. of teeth lost
Figure 1. Incidence rates of cardiovascular events increase linearly
according to number of teeth lost. PY, person-years.
note, edentulous individuals (tooth loss = 28) generally showed
the highest cardiovascular risk, with the exception of MI. The
association between tooth loss and mortality was the strongest.
Increase in 1 missing tooth was associated with a 1.0%, 1.6%,
1.5%, and 2.2% increase in risk for MI, HF, stroke, and death,
respectively.
Associated with Missing Teeth
The association between tooth loss and risk of cardiovascular
events was significant in all subgroup analyses by sex, age,
BMI, underlying diseases, social habits, income, and presence
of periodontitis (Fig. 2). The association between tooth loss and
cardiovascular events was significantly stronger for younger
subjects (age <65 y) and subjects with periodontitis. P value for
interaction was significant for age, presence of periodontitis,
and hypertension in all outcomes. It was also significant for
BMI and dyslipidemia in MI; for dyslipidemia in HF; for sex,
dyslipidemia, and drinking in stroke; and for diabetes mellitus,
smoking, and drinking in death, although there was little differ-
ence in HR values. Income level and exercise habits did not
modify the association between tooth loss and all cardiovascu-
lar outcomes, nor was there a significant interaction for COPD,
a variable that we used to check for spurious association.
Subgroup analyses of cardiovascular risk associated with
≥5 missing teeth showed similar trends (Appendix Fig. 3); the
association with cardiovascular outcomes was significant in
almost all subgroups (except being marginally insignificant for
MI in obesity), with the predictive value of tooth loss for car-
diovascular events being especially stronger among younger
subjects (age <65 y). We also performed analyses for
Tooth Loss Predicts MI, Heart Failure, Stroke, and Death 167

Table 2. Risk of Cardiovascular Events Increase in Proportion to Tooth Loss.

Hazard Ratio (95% CI)

Incidence Rates per 1,000

Event: Tooth Loss Events (Observed), n Person-years Model 1a Model 2b

Myocardial infarction
0 25,966 (3,978,654) 0.85 1 (reference) 1 (reference)
1 to 4 3,689 (329,461) 1.46 1.15 (1.11 to 1.19) 1.08 (1.05 to 1.12)
5 to 14 1,641 (81,337) 2.68 1.24 (1.18 to 1.31) 1.13 (1.08 to 1.19)
15 to 27 461 (12,601) 5.04 1.31 (1.20 to 1.44) 1.24 (1.11 to 1.31)
28 111 (2,917) 5.31 1.15 (0.95 to 1.38) 1.07 (0.89 to 1.29)
Total 31,868 (4,404,970) 0.95 1.015 (1.012 to 1.019)c 1.010 (1.007 to 1.014)c
Heart failure
0 17,882 (3,978,654) 0.59 1 (reference) 1 (reference)
1 to 4 2,611 (329,461) 1.03 1.10 (1.05 to 1.14) 1.04 (0.99 to 1.08)
5 to 14 1,455 (81,337) 2.37 1.28 (1.21 to 1.35) 1.17 (1.11 to 1.23)
15 to 27 517 (12,601) 5.63 1.46 (1.33 to 1.59) 1.39 (1.29 to 1.51)
28 172 (2,917) 8.25 1.66 (1.43 to 1.94) 1.52 (1.31 to 1.77)
Total 22,637 (4,404,970) 0.67 1.021 (1.018 to 1.024)c 1.016 (1.013 to 1.019)c
Stroke
0 24,150 (3,978,654) 0.79 1 (reference) 1 (reference)
1 to 4 3,835 (329,461) 1.52 1.20 (1.16 to 1.24) 1.12 (1.09 to 1.16)
5 to 14 2,110 (81,337) 3.45 1.40 (1.34 to 1.46) 1.26 (1.20 to 1.32)
15 to 27 651 (12,601) 7.16 1.39 (1.29 to 1.51) 1.28 (1.18 to 1.39)
28 195 (2,917) 9.44 1.43 (1.24 to 1.64) 1.30 (1.13 to 1.50)
Total 30,941 (4,404,970) 0.92 1.021 (1.018 to 1.023)c 1.015 (1.012 to 1.018)c
All-cause death
0 52,701 (3,978,654) 1.72 1 (reference) 1 (reference)
1 to 4 8,275 (329,461) 3.27 1.17 (1.14 to 1.19) 1.11 (1.08 to 1.14)
5 to 14 4,763 (81,337) 7.71 1.45 (1.41 to 1.49) 1.28 (1.25 to 1.32)
15 to 27 1,783 (12,601) 19.19 1.81 (1.72 to 1.90) 1.53 (1.46 to 1.61)
28 541 (2,917) 25.51 1.95 (1.79 to 2.12) 1.62 (1.49 to 1.77)
Total 68,063 (4,404,970) 2.01 1.031 (1.029 to 1.032)c 1.022 (1.020 to 1.023)c

Significant P values are in bold (P < 0.05).

a
Model 1 was adjusted for age and sex.
b
Model 2 was adjusted for age, sex, body mass index, diagnosis of diabetes mellitus, hypertension, dyslipidemia, chronic pulmonary disease, end-stage
renal disease, smoking history, drinking history, exercise habits, and low income level.
c
Hazard ratios for 1 increase in tooth loss.

interaction on an additive scale for the cardiovascular risk
associated with ≥5 missing teeth and 1) older age (≥65 y) and
2) presence of periodontitis (Appendix Table 2). There was a
negative interaction between age and tooth loss for MI and a
positive interaction between age and tooth loss for death; oth-
erwise, interaction on an additive scale was insignificant.
In general, there was no substantial difference among sub-
groups except those by age and presence of periodontitis, indi-
cating that residual confounding by sex, socioeconomic status,
smoking, or comorbidities was unlikely to explain the observed
associations between tooth loss and cardiovascular outcomes
in the main analyses.
Discussion
Oral health, represented by the number of missing teeth,
showed a consistently strong and dose-dependent association
with incident MI, HF, ischemic stroke, and mortality in a large
population-based cohort, after adjustment for age, BMI, other
cardiovascular risk factors, and socioeconomic status. The
association seemed to be stronger in the order of MI, HF, and
stroke, with the strongest association for mortality. Increase in
1 missing tooth was associated with an approximately 1%
increase in MI, 1.5% increase in HF, 1.5% increase in stroke,
and 2% increase in mortality. Having ≥5 missing teeth substan-
tially increased risk for cardiovascular outcomes, and even a
small number of missing teeth (1 to 4) was associated with an
increased risk for MI, stroke, and death. Also, this association
was significant in all subgroup analyses and remained strong
after multivariable adjustment, indicating that residual con-
founding by sex, socioeconomic status, smoking, or comor-
bidities was unlikely. To our knowledge, this study of 4,440,970
subjects is the largest study examining the association between
oral health and a variety of cardiovascular outcomes within a single
cohort. To note, the study cohort was relatively young (mean
age, 41.5 y), and there was complete follow-up data for >7 y.
Poor Oral Health and Cardiovascular Outcome
Poor oral health was independently associated with cardiovas-
cular events and mortality in previous studies. Periodontitis
was especially associated with cardiovascular morbidity.
Periodontitis was associated with endothelial dysfunction, a
marker of subclinical atherosclerosis (Gurav 2014), and
168
Figure 2. Subgroup analysis for cardiovascular risk associated with an increase in 1 missing tooth. Hazard ratios are adjusted for age, sex, BMI,
diagnosis of DM, hypertension, dyslipidemia, COPD, end-stage renal disease, smoking history, drinking history, exercise habits, and low-income level.
Significant P values for interaction are in bold (P < 0.05). BMI, body mass index; COPD, chronic obstructive pulmonary disease; DM, diabetes mellitus;
HF, heart failure; HR, hazard ratio; MI, myocardial infarction.
treatment for periodontitis lowered inflammatory mediators
and improved endothelial function (Tonetti et al. 2007).
However, there is insufficient evidence whether periodontitis
treatment is beneficial in decreasing cardiovascular risk (Li et
al. 2017). A case-control study (n = 1,610) demonstrated that
periodontitis verified by radiographic bone loss was associated
with an increased risk for first MI (odds ratio, 1.28; 95% CI,
1.03 to 1.60) (Ryden et al. 2016). A cohort study (n = 8,999;
follow-up, 15.8 y) examined whether parameters of periodon-
tal disease, such as number of deepened pockets, bleeding on
probing, and number of teeth, were associated with cardiovas-
cular outcomes and found that only number of teeth was sig-
nificantly associated with incident MI and HF but not stroke
(Holmlund et al. 2017).
Tooth Loss and Cardiovascular Outcome
Tooth loss is an easily accessible marker of oral health in large-
scale studies, and it represents the end stage of oral diseases
such as caries and periodontitis. Dental caries and periodontal
disease are the main reasons for tooth loss (Hull et al. 1997;
Ravald and Johansson 2012), and the latter is the most com-
mon cause for tooth loss in the older population (Bartova et al.
2014). Measures of periodontitis became more severe as tooth
loss increased, and there was a significant association between
tooth loss levels and subclinical atherosclerosis such as carotid
Journal of Dental Research 98(2)
plaque incidence (Desvarieux et al. 2003). Tooth loss was inde-
pendently associated with an increased incidence of coronary
heart disease and stroke in a cohort of 1,147 men (incidence
odds ratios, 1.5 and 2.8, respectively; Beck et al. 1996).
Another cohort study (44,119 men, 6 y of follow-up) showed
an increased risk of coronary heart disease among men with
<10 teeth as compared with those with ≥25 teeth (adjusted rela-
tive risk [RR], 1.67; 95% CI, 1.03 to 2.71) but only for those
with preexisting periodontal disease (Joshipura et al. 1996). A
cohort of 12,631 young students followed up for 57 y reported
that subjects with ≥9 missing teeth at baseline had an increased
risk of CVD (HR, 1.35; 95% CI, 1.03 to 1.77) versus those
with <5 missing teeth. Other recent studies also showed that
increasing tooth loss was associated with higher CVD risk and
all-cause mortality, except for stroke (Liljestrand et al. 2015;
Joshy et al. 2016); however, in a meta-analysis, periodontitis
(RR, 1.63; 95% CI, 1.25 to 2.00) and tooth loss (RR, 1.39; 95%
CI, 1.13 to 1.65) also increased risk for stroke (Lafon et al.
2014). Also, a recent meta-analysis of 879,084 subjects showed
that an increase of 1 missing tooth was associated with a 1.5%
increment in coronary heart disease risk and a 1.5% increment
in stroke risk, which is consistent with our study results of >4
million subjects (Cheng et al. 2018).
Tooth loss was strongly associated with cardiovascular out-
come in subgroup analyses, but this association was attenuated
for older subjects (age >65 y). This is in line with a previous
Tooth Loss Predicts MI, Heart Failure, Stroke, and Death
systemic review, which found that the association between peri-
odontal disease and atherosclerotic CVD was stronger among
younger adults, and there was no evidence for an association
between periodontal disease and incident coronary heart dis-
ease of subjects >65 y (Dietrich et al. 2013). Age is a strong risk
factor for both CVD and periodontal disease. The elderly have
a higher prevalence of other cardiovascular risk factors as well,
which may explain why the predictive power of tooth loss for
CVD and mortality is diminished in this population. Also, tooth
loss was more strongly linked to adverse outcome among sub-
jects with periodontitis in this study. The reason behind this
may be that tooth loss is likely due to periodontitis in this sub-
population and thus reflects greater inflammation and poor oral
health more than in subjects without periodontitis.
Mechanisms Linking Tooth Loss and CVD
The link between poor oral health, especially tooth loss, and
CVD is consistent, though causality is not definite. The mecha-
nism behind this link may be chronic low-grade inflammation
in the oral tissues, as inflammation contributes to the pathogen-
esis of atherosclerosis (Desvarieux et al. 2003; Lockhart et al.
2012). Periodontal disease induces a chronic low-grade inflam-
mation that eventually damages the dental support tissues and
progresses to tooth loss. Dental caries also leads to penetration
of oral bacteria through the enamel and dentin, causing chronic
infection and inflammation of the dental pulp without treatment
(Farges et al. 2015; Jain and Bahuguna 2015). Inflammatory
mediators released from the inflamed oral tissues can evoke a
chronic systemic low-grade inflammatory response and
enhance atherosclerotic plaque formation (Bartova et al. 2014).
Directly, toothbrushing or dental procedures can cause bactere-
mia (Tomas et al. 2007); oral microorganisms can enter the
bloodstream, causing inflammation and thereby contributing
to atherosclerosis. Oral bacteria such as Porphyromonas gingi-
valis and Aggregatibacter actinomycetemcomitans have been
detected in human atheroma specimens (Ford et al. 2006).
Inflammation is also related to aggravating HF (Wrigley et al.
2011).
Moreover, it may be that individuals with periodontal dis-
ease have a more proinflammatory constitution predisposing
them to CVD (Beck et al. 1996). Edentulous subjects, even in
the absence of all substrates for current inflammation, showed
the highest CVD mortality in previous studies (Watt et al.
2012; Liljestrand et al. 2015). In this study as well, incidence
of all cardiovascular outcomes increased with number of miss-
ing teeth up to the edentulous state. Edentulous subjects (tooth
loss = 28) generally showed the highest cardiovascular risk
(significant for HF, stroke, and death, though not significant
for MI).
Impaired dentition and resulting poor nutritional intake
related to tooth loss were also proposed to contribute to
increased cardiovascular mortality (Hung et al. 2003; Schwahn
et al. 2013; Zhu and Hollis 2014), though a systematic review
found the association between tooth loss and nutritional status
to be weak (Gaewkhiew et al. 2017).
169
Strengths and Limitations
A major strength of this study is its large cohort representative
of the general Korean population. Also, important baseline
characteristics, including known cardiovascular factors and
routine health checkup results, as well as all information on
incident diseases and medical treatment of the study popula-
tion were available for analysis, as NHIS is the single health
insurance provider for the whole Korean population. Finally,
the large number of subjects with a relatively long follow-up
made it possible to investigate various cardiovascular out-
comes with high power in a single cohort.
One limitation is that the simple dental examinations did not
provide information on reasons for tooth loss and severity of
periodontal disease. Tooth loss may have been caused by vari-
ous reasons, such as periodontitis, caries, or trauma. However,
tooth loss is most commonly caused by periodontitis and caries
in the adult population. Also, of various indices of periodontal
disease severity, number of teeth showed the strongest associa-
tion with cardiovascular outcome (Holmlund et al. 2017).
Second, we used only income as a variable to represent socio-
economic status in multivariable adjustment because other
information, such as occupation or educational status, was
unavailable from the database, and there may be some residual
confounding related to socioeconomic status. Third, the diagno-
ses of MI, HF, and stroke were based on ICD-10 codes, and
there may be some under- or overestimation versus the actual
disease incidence. However, these definitions were used in pre-
vious studies, including one by our group (Park et al. 2018);
also, defining comorbidities and outcomes through the use of
diagnostic codes and prescription data from claims databases
was validated in previous studies from countries with similar
health insurance systems (Cheng et al. 2011; Cheng et al. 2014;
Park and Choi 2016), and routinely collected nationwide claims
data were shown to be a valid resource for population research
of CVD. Fourth, we could not analyze the risk of cardiovascular
death, because the cause of death could not be identified in this
claims database. We reported all-cause mortality as a hard end-
point instead of cardiovascular death. Fifth, the association
between tooth loss and cardiovascular outcome does not mean
causality, and further studies are needed to know whether dental
interventions to improve oral health and prevent tooth loss can
reduce cardiovascular risk. Finally, as the present study was
performed with an Asian population, generalizability to other
ethnicities is unknown.
Conclusion
In conclusion, in this large nationwide cohort study represent-
ing the Korean population, we found tooth loss, representing
oral health, showed a dose-dependent association with incident
MI, HF, ischemic stroke, and all-cause death and was a good
predictor of cardiovascular outcome. This association was
consistent in multivariable and subgroup analyses. In clinical
practice, the number of missing teeth can aid physicians in dis-
criminating patients with a higher cardiovascular risk.
170
Author Contributions
H.J. Lee, contributed to design, data analysis and interpretation,
drafted the manuscript; E.K. Choi, contributed to conception,
design, data acquisition and interpretation, critically revised the
manuscript; J.B. Park, S. Oh, contributed to data interpretation,
critically revised the manuscript; K.D. Han, contributed to con-
ception, design, data acquisition and analysis, critically revised the
manuscript. All authors gave final approval and agree to be
accountable for all aspects of the work.
Acknowledgments
This work was supported by the SNUH Research Fund (grant
062018245); the National Research Foundation of Korea, funded
by the Ministry of Education, Science, and Technology (2014R1
A1A2A16055218); and by the Technology Innovation Program
(10052668), funded by the Ministry of Trade, Industry and Energy
(Korea). The authors declare no potential conflicts of interest with
respect to the authorship and/or publication of this article.
ORCID iD
E.K. Choi https://orcid.org/0000-0002-0411-6372
References
Bartova J, Sommerova P, Lyuya-Mi Y, Mysak J, Prochazkova J, Duskova J,
Janatova T, Podzimek S. 2014. Periodontitis as a risk factor of atheroscle-
rosis. J Immunol Res. 2014:636893.
Beck J, Garcia R, Heiss G, Vokonas PS, Offenbacher S. 1996. Periodontal dis-
ease and cardiovascular disease. J Periodontol. 67(10 Suppl):1123–1137.
Cheng CL, Kao YH, Lin SJ, Lee CH, Lai ML. 2011. Validation of the national
health insurance research database with ischemic stroke cases in Taiwan.
Pharmacoepidemiol Drug Saf. 20(3):236–242.
Cheng CL, Lee CH, Chen PS, Li YH, Lin SJ, Yang YH. 2014. Validation of
acute myocardial infarction cases in the national health insurance research
database in Taiwan. J Epidemiol. 24(6):500–507.
Cheng F, Zhang M, Wang Q, Xu H, Dong X, Gao Z, Chen J, Wei Y, Qin
F. 2018. Tooth loss and risk of cardiovascular disease and stroke: a
dose-response meta analysis of prospective cohort studies. PLoS One.
13(3):e0194563.
Desvarieux M, Demmer RT, Rundek T, Boden-Albala B, Jacobs DR, Jr.,
Papapanou PN, Sacco RL; Oral I; Vascular Disease Epidemiology Study.
2003. Relationship between periodontal disease, tooth loss, and carotid
artery plaque: the Oral Infections and Vascular Disease Epidemiology
Study (INVEST). Stroke. 34(9):2120–2125.
Dietrich T, Sharma P, Walter C, Weston P, Beck J. 2013. The epidemiological
evidence behind the association between periodontitis and incident athero-
sclerotic cardiovascular disease. J Periodontol. 84(4):S70–S84.
Eke PI, Dye BA, Wei L, Slade GD, Thornton-Evans GO, Borgnakke WS,
Taylor GW, Page RC, Beck JD, Genco RJ. 2015. Update on prevalence
of periodontitis in adults in the United States: NHANES 2009 to 2012.
J Periodontol. 86(5):611–622.
Farges JC, Alliot-Licht B, Renard E, Ducret M, Gaudin A, Smith AJ, Cooper
PR. 2015. Dental pulp defence and repair mechanisms in dental caries.
Mediators Inflamm. 2015:230251.
Ford PJ, Gemmell E, Chan A, Carter CL, Walker PJ, Bird PS, West MJ,
Cullinan MP, Seymour GJ. 2006. Inflammation, heat shock proteins and
periodontal pathogens in atherosclerosis: an immunohistologic study. Oral
Microbiol Immunol. 21(4):206–211.
Gaewkhiew P, Sabbah W, Bernabe E. 2017. Does tooth loss affect dietary
intake and nutritional status? A systematic review of longitudinal studies.
J Dent. 67:1–8.
Gurav AN. 2014. The implication of periodontitis in vascular endothelial dys-
function. Eur J Clin Invest. 44(10):1000–1009.
Holmlund A, Lampa E, Lind L. 2017. Oral health and cardiovascular disease
risk in a cohort of periodontitis patients. Atherosclerosis. 262:101–106.
Hong JW, Noh JH, Kim DJ. 2016. The prevalence and associated factors of
periodontitis according to fasting plasma glucose in the korean adults: the
Journal of Dental Research 98(2)
2012–2013 Korea National Health and Nutrition Examination Survey.
Medicine (Baltimore). 95(14):e3226.
Hull PS, Worthington HV, Clerehugh V, Tsirba R, Davies RM, Clarkson
JE. 1997. The reasons for tooth extractions in adults and their validation.
J Dent. 25(3–4):233–237.
Hung HC, Willett W, Ascherio A, Rosner BA, Rimm E, Joshipura KJ. 2003.
Tooth loss and dietary intake. J Am Dent Assoc. 134(9):1185–1192.
Jain A, Bahuguna R. 2015. Role of matrix metalloproteinases in dental caries,
pulp and periapical inflammation: an overview. J Oral Biol Craniofac Res.
5(3):212–218.
Joshipura KJ, Rimm EB, Douglass CW, Trichopoulos D, Ascherio A, Willett
WC. 1996. Poor oral health and coronary heart disease. J Dent Res.
75(9):1631–1636.
Joshy G, Arora M, Korda RJ, Chalmers J, Banks E. 2016. Is poor oral health a
risk marker for incident cardiovascular disease hospitalisation and all-cause
mortality? Findings from 172 630 participants from the prospective 45 and
up study. BMJ Open. 6(8):e012386.
Lafon A, Pereira B, Dufour T, Rigouby V, Giroud M, Bejot Y, Tubert-Jeannin
S. 2014. Periodontal disease and stroke: a meta-analysis of cohort studies.
Eur J Neurol. 21(9):1155–1161, e66–e67.
Lee H, Choi EK, Lee SH, Han KD, Rhee TM, Park CS, Lee SR, Choe WS, Lim
WH, Kang SH, et al. 2017. Atrial fibrillation risk in metabolically healthy
obesity: a nationwide population-based study. Int J Cardiol. 240:221–227.
Lee HY, Choi YH, Park HW, Lee SG. 2012. Changing patterns in the asso-
ciation between regional socio-economic context and dental caries experi-
ence according to gender and age: a multilevel study in Korean adults. Int
J Health Geogr. 11:30.
Lee JH, Lee JS, Park JY, Choi JK, Kim DW, Kim YT, Choi SH. 2015.
Association of lifestyle-related comorbidities with periodontitis: a nation-
wide cohort study in Korea. Medicine (Baltimore). 94(37):e1567.
Li C, Lv Z, Shi Z, Zhu Y, Wu Y, Li L, Iheozor-Ejiofor Z. 2017. Periodontal
therapy for the management of cardiovascular disease in patients with
chronic periodontitis. Cochrane Database Syst Rev. 11:CD009197.
Liljestrand JM, Havulinna AS, Paju S, Männistö S, Salomaa V, Pussinen PJ.
2015. Missing teeth predict incident cardiovascular events, diabetes, and
death. J Dent Res. 94(8):1055–1062.
Lockhart PB, Bolger AF, Papapanou PN, Osinbowale O, Trevisan M, Levison
ME, Taubert KA, Newburger JW, Gornik HL, Gewitz MH, et al. 2012.
Periodontal disease and atherosclerotic vascular disease: does the evi-
dence support an independent association? A scientific statement from the
American Heart Association. Circulation. 125(20):2520–2544.
Park CS, Choi EK, Han KD, Lee HJ, Rhee TM, Lee SR, Cha MJ, Lim WH,
Kang SH, Oh S. 2018. Association between adult height, myocardial infarc-
tion, heart failure, stroke and death: a Korean nationwide population-based
study. Int J Epidemiol. 47(1):289–298.
Park TH, Choi JC. 2016. Validation of stroke and thrombolytic therapy in
Korean national health insurance claim data. J Clin Neurol. 12(1):42–48.
Ravald N, Johansson CS. 2012. Tooth loss in periodontally treated patients: a
long-term study of periodontal disease and root caries. J Clin Periodontol.
39(1):73–79.
Ryden L, Buhlin K, Ekstrand E, de Faire U, Gustafsson A, Holmer J, Kjellstrom
B, Lindahl B, Norhammar A, Nygren A, et al. 2016. Periodontitis increases
the risk of a first myocardial infarction: a report from the parokrank study.
Circulation. 133(6):576–583.
Schwahn C, Polzer I, Haring R, Dorr M, Wallaschofski H, Kocher T, Mundt
T, Holtfreter B, Samietz S, Volzke H, et al. 2013. Missing, unreplaced
teeth and risk of all-cause and cardiovascular mortality. Int J Cardiol.
167(4):1430–1437.
Tomas I, Alvarez M, Limeres J, Potel C, Medina J, Diz P. 2007. Prevalence,
duration and aetiology of bacteraemia following dental extractions. Oral
Dis. 13(1):56-62.
Tonetti MS, D’Aiuto F, Nibali L, Donald A, Storry C, Parkar M, Suvan J,
Hingorani AD, Vallance P, Deanfield J. 2007. Treatment of periodontitis
and endothelial function. N Engl J Med. 356(9):911–920.
Tu YK, Galobardes B, Smith GD, McCarron P, Jeffreys M, Gilthorpe MS.
2007. Associations between tooth loss and mortality patterns in the
Glasgow Alumni Cohort. Heart. 93(9):1098–1103.
Watt RG, Tsakos G, de Oliveira C, Hamer M. 2012. Tooth loss and cardiovas-
cular disease mortality risk—results from the Scottish Health Survey. PLoS
One. 7(2):e30797.
Wrigley BJ, Lip GY, Shantsila E. 2011. The role of monocytes and inflammation
in the pathophysiology of heart failure. Eur J Heart Fail. 13(11):1161–1171.
Zhang Q, Li Z, Wang C, Shen T, Yang Y, Chotivichien S, Wang L. 2014.
Prevalence and predictors for periodontitis among adults in China, 2010.
Glob Health Action. 7:24503.
Zhu Y, Hollis JH. 2014. Tooth loss and its association with dietary intake and
diet quality in American adults. J Dent. 42(11):1428–1435.