- Email: [email protected]
Risk of peripheral arterial disease in patients with periodontitis: A nationwide, population-based, matched cohort study
Atherosclerosis 297 (2020) 96–101
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Risk of peripheral arterial disease in patients with periodontitis: A nationwide, population-based, matched cohort study
T
Dong-Hyuk Choa,1, In-Seok Songb,1, Jimi Choic, Jun Gyo Gwond,∗ a
Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea Department of Oral and Maxillofacial Surgery, Korea University College of Medicine, Seoul, Republic of Korea c Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea d Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Republic of Korea b
HIGHLIGHTS
with periodontitis have a high incidence of peripheral arterial disease. • Patients oral hygiene risk factors increase the risk of peripheral arterial disease. • Poor • Control of periodontitis is important for preventing peripheral arterial disease. ARTICLE INFO
ABSTRACT
Keywords: Periodontitis Peripheral arterial disease Cardiovascular disease Atherosclerosis Inflammation Oral health
Background and aims: The association between coronary heart disease (CHD) caused by atherosclerosis and periodontitis has already been established. Peripheral arterial disease (PAD) is also caused by atherosclerosis, but the characteristics of the target artery and the disease are different from those of CHD. The aim of this study was to determine whether the risk of PAD was high in patients with periodontitis. Methods: For this study, we used data from the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) database that were collected between January 2003 and December 2014. We compared the incidence of PAD between patients with periodontitis and a matched control group selected from among 514,832 people enrolled in the NHIS-HEALS database to confirm the increased incidence of PAD in patients with periodontitis. Results: The incidence per 1000 person-years was 2.40 in the patients with periodontitis and 2.08 in the matched controls. The hazard ratio (HR) of PAD in the periodontitis group compared with that in the matched group was 1.15 (95% confidence interval, 1.07–1.23). In the subgroup analysis, sex, age, smoking, and hypertension statistically modified the influence of periodontitis on PAD risk. Conclusions: Control of periodontitis is important in the prevention of PAD, in addition to correcting conventional risk factors such as diabetes mellitus, hypertension, dyslipidemia, and smoking.
1. Introduction Atherosclerotic vascular disease, including coronary heart disease (CHD) and peripheral arterial disease (PAD), is the result of ischemia that occurs in the involved artery. Atherosclerosis was previously thought to be simple luminal bulging caused by fatty deposits in the arterial wall. However, currently, a process of inflammatory response from the development of fat streaks to the occurrence of acute events due to plaque erosion or rupture is recognized [1]. Periodontitis is a
chronic inflammatory disease of the tooth-supporting tissues [2]. It may result in a systemic inflammatory response and is one of the most common chronic infections [3]. Thus, the progression of atherosclerosis is thought to be more severe in patients with periodontitis. In fact, many studies have reported a higher incidence of CHD in patients with periodontitis [4–7]. As both CHD and PAD are atherosclerosis-related diseases, the risk factors of onset and disease progression are the same. However, the odds ratio of each risk factor of onset and progression varies depending on the disease. This may be because the function and
Corresponding author. Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Koryudae-ro 73, Seongbuk-gu, 02841, Seoul, Republic of Korea. E-mail address: [email protected] (J.G. Gwon). 1 These authors contributed equally to this work. ∗
https://doi.org/10.1016/j.atherosclerosis.2020.02.012 Received 16 September 2019; Received in revised form 2 January 2020; Accepted 13 February 2020 Available online 15 February 2020 0021-9150/ © 2020 Elsevier B.V. All rights reserved.
Atherosclerosis 297 (2020) 96–101
D.-H. Cho, et al.
location of the involved arteries are different for each disease. For example, Philipp et al. reported that systemic inflammation is more relevant in PAD than in stable coronary artery disease [8]. Jang et al. reported that PAD has less relevance to obesity than CHD [9]. Although many studies on the relationship between CHD and periodontitis have been conducted, no report has described the relationship between PAD and periodontitis. The aim of this study was to determine whether the risk of PAD is high in patients with periodontitis.
periodontitis. Propensity score was calculated through a multiple logistic regression model that included the presence of periodontitis as a dependent variable and all of the variables mentioned in Table 1 as independent variables. We used greedy nearest neighbor matching on the logit of the propensity score by using calipers with a width of 0.2 of the standard deviation of the logit of the propensity score. The balance between the two matched groups was evaluated using an absolute standardized difference of < 0.1. The incidence rate of PAD was calculated by dividing the number of events by the person-years at risk. The relative hazard ratio (HR) of PAD in the patients with periodontitis compared with that in the matched control group was estimated using Cox proportional hazards model with a robust variance estimator and presented with 95% confidence intervals. Cumulative incidences of PAD in patients with periodontitis and controls were plotted using the Kaplan-Meier method. We performed a time-dependent receiver-operating characteristic (ROC) curve analysis to assess the predictive power of periodontitis and the covariates for the incidence of PAD. The ROC curves were presented at 2-year intervals since study enrollment. A p value of < 0.05 was considered statistically significant. Data were analyzed using the SAS version 9.4 software (SAS Institute, Cary, NC, USA).
2. Patients and methods 2.1. Study design and database We compared the incidence of PAD in patients with periodontitis with that in a control group. This was a retrospective matched cohort study that investigated the records of representative patients that were obtained from the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) database. The entire Korean population is covered by the NHIS. However, owing to the large volume of the database and the lack of confidentiality regarding personal information available in the NHIS database, the NHIS-HEALS was modeled as a representative-sample database containing a substantial volume of representative information that does not require privacy regulations. This database included 514,832 citizens of the Republic of Korea who were between 40 and 79 years of age. This represents 10% of a random selection of all health screening participants in the index year 2002 or 2003 who were followed up until 2015. The detailed cohort protocol was described previously [10]. We obtained information on 514,832 individuals from the NHIS-HEALS database between January 1, 2003, and December 31, 2014, for our study. Of the patients diagnosed as having periodontitis during the study period, those who had been previously diagnosed as having periodontitis and those who had been diagnosed as having atherosclerotic vascular disease were excluded from the study. The control group was selected from among those who had never been diagnosed as having periodontitis during the study period and matched 1:1 to the patients with periodontitis using the propensity score matching method. Age, sex, region, insurance, body mass index (BMI), smoking history, alcohol consumption, exercise, hypertension (HTN), diabetes mellitus (DM), dyslipidemia, medication history (DM medication, HTN medication, statins, and anti-thrombotic agents), and diagnostic codes according to the International Classification of Diseases, Tenth Revision (ICD-10), were recorded. This study was approved by the ethics committee of Korea University Anam Hospital (2018AN0253). The flowchart of the study is summarized in Fig. 1.
3. Results Of the 514,832 people enrolled in the NHIS-HEALS database between January 2003 and December 2014, 72,971 patients with periodontitis were identified. The clinical characteristics of the study group and the 1:1 matched group are shown in Table 1. The prevalence of smoking in the periodontitis and matched control groups was 37.6%. The incidence rates of HTN were 21.4% and 21.7%, respectively. The incidence rates of DM were 6.1% and 5.6%, respectively; and those of dyslipidemia, 4.8% and 5.2%, respectively. The median follow-up period of the patients was 126.1 months (interquartile range, 102.2–138.2 months). During the follow-up period, 1733 patients (3.35%) developed PAD from among those with periodontitis. In the matched group, PAD occurred in 1435 patients (2.73%). The mean ages of the patients with PAD in the periodontitis and matched groups were 64.9 ± 9.4 and 66.8 ± 10.3 years, respectively. The incidence per 1000 person-years was 2.40 in the periodontitis group and 2.08 in the matched control group (Table 2). Fig. 2 shows the cumulative incidence of PAD in the periodontitis and matched control groups during the follow-up period. The HR of PAD in the periodontitis group compared with that in the matched group was 1.15 (95% confidence interval [CI], 1.07–1.23). In the time-dependent ROC curves, the areas under the curve identified every 24 months were 69.8, 71.3, 70.1, 69.9, 70.8, and 68.5, respectively (Fig. 3). Fig. 4 shows the risk of PAD associated with periodontitis exposure among the various subgroups according to the risk factors of atherosclerosis and the clinical data. In the subgroup analysis, sex, age, smoking, drinking, and HTN significantly modified the influence of periodontitis on PAD risk (p for interaction = 0.008, < 0.001, < 0.001, 0.029, and 0.007, respectively). In the periodontitis group, compared with the matched control group, male sex, young age (< 60 years), smoking, alcohol drinking, and absence of HTN, DM, and dyslipidemia were statistically significant factors in PAD incidence (HR, 95% CI: 1.27, 1.15–1.41; 1.41, 1.27–1.55; 1.48, 1.30–1.68; 1.30, 1.15–1.47; 1.25, 1.14–1.36; 1.16, 1.08–1.28; and 1.16, 1.08–1.25, respectively). BMI and regular exercise showed statistically significant effects on the incidence of PAD regardless of severity.
2.2. Definition of the clinical variables Patients from the NHIS-HEALS with ICD-10 codes K05.2–3 (periodontitis) were identified. Patients with comorbidities were defined as those with HTN (ICD-10 codes I10-13 and I15), DM (ICD-10 codes E1114), dyslipidemia (ICD-10 codes E78), ischemic heart disease (ICD-10 codes I21 and I22), stroke (ICD-10 codes I63), and PAD (ICD-10 codes I70, I70.0, I70.2–70.3, I70.8–70.9, I74.2–74.5). The definition of a current drinker was someone who drank more than once a week. Regular exercise was defined as exercise more than three times a week. To improve the accuracy of the analysis, we only included patients with at least two principal diagnostic codes for each disease. The date of disease diagnosis was used as the entry date for patients with the disease. The definition of medication use was limited to a medication prescription for more than 30 days after the time of the reference date.
4. Discussion
2.3. Statistical analyses
4.1. Mechanism of the relationship between periodontitis and PAD
Continuous variables were presented as mean (standard deviation), and categorical variables were described as numbers with percentages. Propensity score matching was performed in subjects with and without
According to recent studies, two indirect mechanisms and one direct mechanism can be assumed in the association between periodontitis and the incidence of PAD [11,12]. The first indirect mechanism is the 97
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Fig. 1. Flowchart of the study population selection. Table 1 Baseline characteristics. Variables
Periodontitis cases (n = 72,971)
Matched controls (n = 72,971)
ASD
Age (years), mean (SD) Male, n (%) Smoking, ever n (%) Current drinker, n (%) Regular exercise, n (%) Body mass index, mean (SD) Comorbidity Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Medication Antidiabetics Oral hypoglycemic agents, n (%) Insulin, n (%) Antihypertensives Inhibitors of the renin-angiotensin system, n (%) Calcium channel blocker, n (%) α-Blockers, n (%) β-Blockers, n (%) Diuretics, n (%) Vasodilators, n (%) Statins, n (%)
54.9 (8.9) 40,655 (55.7) 27,435 (37.6) 29,885 (41.0) 19,677 (27.0) 23.8 (2.8)
55.1 (10.4) 40,655 (55.7) 27,435 (37.6) 30,283 (41.5) 18,806 (25.8) 23.7 (3.0)
0.011 < .001 < .001 0.011 0.027 0.036
15,635 (21.4) 4414 (6.1) 3475 (4.8)
15,814 (21.7) 4108 (5.6) 3789 (5.2)
0.006 0.018 0.020
3610 (5.0) 200 (0.3)
3253 (4.5) 173 (0.2)
0.023 0.007
4810 (6.6) 8077 (11.1) 2392 (3.3) 5391 (7.4) 6801 (9.3) 10 (0.01) 3190 (4.4)
4750 (6.5) 7918 (10.9) 2696 (3.7) 5302 (7.3) 6946 (9.5) 11 (0.02) 3435 (4.7)
0.003 0.007 0.023 0.005 0.007 0.001 0.016
ASD, absolute standardized difference. Comorbidity: disease identified more than once with the main diagnostic code by the reference date. Medication: prescribed medication for ≥30 days from the base date.
development and progression of atherosclerosis by systemic inflammation. Proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL) 1, and IL-6 induce the production of C-reactive protein and fibrinogen in the liver, which leads to atherogenesis [13,14]. In fact, anti-inflammatory treatment with canakinumab therapy in atherosclerotic disease has shown significantly lower
incidence rates of recurrent cardiovascular events corresponding to the decreased C-reactive protein levels [15]. A second indirect mechanism is the molecular mimicry theory. Molecular mimicry occurs when similarities between foreign and self-peptides produce cross activation of auto-reactive T or B cells [16]. Cross-reactive autoantibodies to periodontal bacterial lipopolysaccharides and heat shock proteins (HSP) 98
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Table 2 Relative risk of peripheral arterial disease in the patients with periodontitis compared with that in the controls.
No. of events Cumulative incidence (%) Incidence rate per 1000 person-years HR (95% CI)
Periodontitis cases (n = 72,971)
Matched controls (n = 72,971)
p
1733 3.35 2.40 1.15 (1.07–1.23)
1435 2.73 2.08 1.00
< .001
Fig. 2. Cumulative incidence of periodontitis in the patient and matched control groups between 2003 and 2014.
Fig. 3. Confounder-adjusted time-dependent ROC curves for PAD risk according to the presence of periodontitis.
99
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Fig. 4. Risk of peripheral arterial disease with or without periodontitis in the subgroups as stratified by other covariates.
have been identified [17,18]. The autoantibodies generated by bacterial lipopolysaccharides and HSP also cause an immune response to HSP 60, resulting in endothelial damage [19]. A direct mechanism in the association between periodontitis and PAD can be explained by the bacteremia caused by periodontal pathogens. In fact, bacteremia is a common daily event during chewing or tooth brushing [20]. After transient bacteremia, pathogens from a periodontal location circulate either within phagocytic cells or extracellularly and deposited in atherosclerotic lesions [21].
difference in the incidence of PAD was found between the periodontitis and control groups of female, old, non-smoking, and non-currently drinking patients. The male, young, smoking, and drinking subgroups all corresponded to the relatively poor oral hygiene conditions [22–24]. These results are probably due to the synergistic effects of poor oral hygiene and periodontitis. The association between younger age and higher risk of atherosclerotic vascular disease under the setting of periodontitis than that in older patients has a different explanation. Invasive periodontal treatment is more common in elderly patients and has the effect of lowering the risk of long-term atherosclerotic vascular disease [25,26]. Paradoxically, the incidence of PAD was found to be higher with periodontitis in the group without HTN, DM, and dyslipidemia, which are obvious risk factors of PAD. This may be because the effects of HTN, DM, and dyslipidemia, which are conventional risk factors of PAD, overwhelm the influence of periodontitis on PAD.
4.2. Effect of periodontitis on PAD risk according to patient condition A subgroup analysis revealed that the incidence of PAD was increased when periodontitis was present in male, young (< 60 years old), smoking, and currently drinking patients. However, no significant 100
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4.3. Limitations
[8] P. Rein, C.H. Saely, G. Silbernagel, A. Vonbank, R. Mathies, et al., Systemic inflammation is higher in peripheral artery disease than in stable coronary artery disease, Atherosclerosis 239 (2) (2015) 299–303. [9] S.Y. Jang, E.Y. Ju, S.I. Cho, S.W. Lee, D.K. Kim, Comparison of cardiovascular risk factors for peripheral artery disease and coronary artery disease in the Korean population, Korean Circ. J. 43 (5) (2013) 316–328. [10] S.C. Seong, Y.Y. Kim, S.K. Park, Y.H. Khang, H.C. Kim, et al., Cohort profile: the national health insurance service-national health screening cohort (NHIS-HEALS) in Korea, BMJ Open 7 (9) (2017) e016640. [11] S.Y. Park, S.H. Kim, S.H. Kang, C.H. Yoon, H.J. Lee, et al., Improved oral hygiene care attenuates the cardiovascular risk of oral health disease: a population-based study from Korea, Eur. Heart J. 40 (14) (2019) 1138–1145. [12] P.B. Lockhart, A.F. Bolger, P.N. Papapanou, O. Osinbowale, M. Trevisan, et al., Periodontal disease and atherosclerotic vascular disease: does the evidence support an independent association?: a scientific statement from the American Heart Association, Circulation 125 (20) (2012) 2520–2544. [13] P.P. Hujoel, B.A. White, R.I. Garcia, M.A. Listgarten, The dentogingival epithelial surface area revisited, J. Periodontal. Res. 36 (1) (2001) 48–55. [14] P. Libby, P.M. Ridker, G.K. Hansson, L.T.N. Ather, Inflammation in atherosclerosis from pathophysiology to practice, J. Am. Coll. Cardiol. 54 (23) (2009) 2129–2138. [15] P.M. Ridker, B.M. Everett, T. Thuren, J.G. MacFadyen, W.H. Chang, et al., Antiinflammatory therapy with canakinumab for atherosclerotic disease, N. Engl. J. Med. 377 (12) (2017) 1119–1131. [16] A.P. Kohm, K.G. Fuller, S.D. Miller, Mimicking the way to autoimmunity: an evolving theory of sequence and structural homology, Trends Microbiol. 11 (3) (2003) 101–105. [17] Y.H.P. Chun, K.R.J. Chun, D. Olguin, H.L. Wang, Biological foundation for periodontitis as a potential risk factor for atherosclerosis, J. Periodontal. Res. 40 (1) (2005) 87–95. [18] D.W. Paquette, The periodontal-cardiovascular link, Comp. Cont. Educ. Dent. 25 (9) (2004) 681–682 685–692; quiz 694. [19] C. Grundtman, S.B. Kreutmayer, G. Almanzar, M.C. Wick, G. Wick, Heat shock protein 60 and immune inflammatory responses in atherosclerosis, Arterioscl. Throm. Vas. 31 (5) (2011) 960–U938. [20] P.B. Lockhart, M.T. Brennan, M. Thornhill, et al., Poor oral hygiene as a risk factor for infective endocarditis-related bacteremia, J. Am. Dent. Assoc. 140 (10) (2009) 1238–1244. [21] P.B. Lockhart, M.T. Brennan, H.C. Sasser, P.C. Fox, B.J. Paster, F.K. BahraniMougeot, Bacteremia associated with toothbrushing and dental extraction, Circulation 117 (24) (2008) 3118–3125. [22] S.M. Strauss, L.B. Stefanou, Interdental cleaning among persons with diabetes: relationships with individual characteristics, Int. J. Dent. Hyg. 12 (2) (2014) 127–132. [23] B. Tseveenjav, A.L. Suominen, M.M. Vehkalahti, Oral health-related behaviours among dentate adults in Finland: findings from the Finnish Health 2000 Survey, Eur. J. Oral Sci. 120 (1) (2012) 54–60. [24] W. Skorupka, K. Zurek, T. Kokot, E. Nowakowska-Zajdel, E. Fatyga, et al., Assessment of oral hygiene in adults, Cent. Eur. J. Publ. Health 20 (3) (2012) 233–236. [25] C. Minassian, F. D'Aiuto, A.D. Hingorani, L. Smeeth, Invasive dental treatment and risk for vascular events a self-controlled case series, Ann. Intern. Med. 153 (8) (2010) 499–506. [26] G. Aarabi, J. Eberhard, D.R. Reissmann, G. Heydecke, U. Seedorf, Interaction between periodontal disease and atherosclerotic vascular disease—fact or fiction? Atherosclerosis 241 (2) (2015) 555–560. [27] D.Y. Chen, C.H. Lin, Y.M. Chen, H.H. Chen, Risk of atrial fibrillation or flutter associated with periodontitis: a nationwide, population-based, cohort study, PloS One 11 (10) (2016) e0165601. [28] C.W. Tsao, C.Y. Liu, T.L. Cha, S.T. Wu, S.C. Chen, C.Y. Hsu, Exploration of the association between chronic periodontal disease and erectile dysfunction from a population-based view point, Andrologia 47 (5) (2015) 513–518. [29] N.S. Tzeng, C.H. Chung, C.B. Yeh, R.Y. Huang, D.Y. Yuh, et al., Are chronic periodontitis and gingivitis associated with dementia? A nationwide, retrospective, matched-cohort study in Taiwan, Neuroepidemiology 47 (2) (2016) 82–93.
This study has some limitations. The diagnoses of the diseases, including periodontitis and PAD, could be inaccurate. The data used in this study were based on the physician's input of the disease name as classified according to the ICD-10. Therefore, objective data are lacking as to why the physicians in charge diagnosed any particular disease. However, the Korean NHIS routinely and randomly samples patient charts to check the accuracy of the diagnosis in all medical institutions to prevent the overcharging of medical insurance reimbursement. The database could also not provide information on other risk factors of PAD, such as family history and C-reactive protein levels. However, most of the existing nationwide studies are based on comorbidity risk factor data, including DM and HTN. The data mainly used are information obtained using ICD codes; this study includes health-related behaviors such as smoking, drinking, and exercise [27–29]. In conclusion, this study revealed that the incidence of PAD increased in the patients with periodontitis. Thus, the control of periodontitis plays an important role in the prevention of PAD, in addition to correcting conventional risk factors such as DM, HTN, dyslipidemia, and smoking. Author contributions Gwon designed the study. Choi performed the statistical analysis. Cho and Song analyzed the data and wrote the manuscript with input from all the authors. Gwon conceived the study and were in charge of the overall direction and planning. Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. References [1] R.R. Packard, P. Libby, Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction, Clin. Chem. 54 (1) (2008) 24–38. [2] B.L. Pihlstrom, B.S. Michalowicz, N.W. Johnson, Periodontal diseases, Lancet 366 (9499) (2005) 1809–1820. [3] K. El Kholy, R.J. Genco, T.E. Van Dyke, Oral infections and cardiovascular disease, Trends Endocrinol. Metabol. 26 (6) (2015) 315–321. [4] G.M. Hansen, A. Egeberg, P. Holmstrup, P.R. Hansen, Relation of periodontitis to risk of cardiovascular and all-cause mortality (from a Danish Nationwide Cohort Study), Am. J. Cardiol. 118 (4) (2016) 489–493. [5] T. Senba, Y. Kobayashi, K. Inoue, C. Kaneto, M. Inoue, et al., The association between self-reported periodontitis and coronary heart disease—from MY Health up Study, J. Occup. Health 50 (3) (2008) 283–287. [6] J.D. Beck, P. Eke, G. Heiss, D. Couper, D. Lin, et al., Periodontal disease and coronary heart disease: a reappraisal of the exposure, Circulation 112 (1) (2005) 19–24. [7] J.R. Elter, C.M.E. Champagne, S. Offenbacher, J.D. Beck, Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease, J. Periodontol. 75 (6) (2004) 782–790.
101
Contents lists available at ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Risk of peripheral arterial disease in patients with periodontitis: A nationwide, population-based, matched cohort study
T
Dong-Hyuk Choa,1, In-Seok Songb,1, Jimi Choic, Jun Gyo Gwond,∗ a
Department of Internal Medicine, Korea University College of Medicine, Seoul, Republic of Korea Department of Oral and Maxillofacial Surgery, Korea University College of Medicine, Seoul, Republic of Korea c Department of Biostatistics, Korea University College of Medicine, Seoul, Republic of Korea d Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Seoul, Republic of Korea b
HIGHLIGHTS
with periodontitis have a high incidence of peripheral arterial disease. • Patients oral hygiene risk factors increase the risk of peripheral arterial disease. • Poor • Control of periodontitis is important for preventing peripheral arterial disease. ARTICLE INFO
ABSTRACT
Keywords: Periodontitis Peripheral arterial disease Cardiovascular disease Atherosclerosis Inflammation Oral health
Background and aims: The association between coronary heart disease (CHD) caused by atherosclerosis and periodontitis has already been established. Peripheral arterial disease (PAD) is also caused by atherosclerosis, but the characteristics of the target artery and the disease are different from those of CHD. The aim of this study was to determine whether the risk of PAD was high in patients with periodontitis. Methods: For this study, we used data from the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) database that were collected between January 2003 and December 2014. We compared the incidence of PAD between patients with periodontitis and a matched control group selected from among 514,832 people enrolled in the NHIS-HEALS database to confirm the increased incidence of PAD in patients with periodontitis. Results: The incidence per 1000 person-years was 2.40 in the patients with periodontitis and 2.08 in the matched controls. The hazard ratio (HR) of PAD in the periodontitis group compared with that in the matched group was 1.15 (95% confidence interval, 1.07–1.23). In the subgroup analysis, sex, age, smoking, and hypertension statistically modified the influence of periodontitis on PAD risk. Conclusions: Control of periodontitis is important in the prevention of PAD, in addition to correcting conventional risk factors such as diabetes mellitus, hypertension, dyslipidemia, and smoking.
1. Introduction Atherosclerotic vascular disease, including coronary heart disease (CHD) and peripheral arterial disease (PAD), is the result of ischemia that occurs in the involved artery. Atherosclerosis was previously thought to be simple luminal bulging caused by fatty deposits in the arterial wall. However, currently, a process of inflammatory response from the development of fat streaks to the occurrence of acute events due to plaque erosion or rupture is recognized [1]. Periodontitis is a
chronic inflammatory disease of the tooth-supporting tissues [2]. It may result in a systemic inflammatory response and is one of the most common chronic infections [3]. Thus, the progression of atherosclerosis is thought to be more severe in patients with periodontitis. In fact, many studies have reported a higher incidence of CHD in patients with periodontitis [4–7]. As both CHD and PAD are atherosclerosis-related diseases, the risk factors of onset and disease progression are the same. However, the odds ratio of each risk factor of onset and progression varies depending on the disease. This may be because the function and
Corresponding author. Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Koryudae-ro 73, Seongbuk-gu, 02841, Seoul, Republic of Korea. E-mail address: [email protected] (J.G. Gwon). 1 These authors contributed equally to this work. ∗
https://doi.org/10.1016/j.atherosclerosis.2020.02.012 Received 16 September 2019; Received in revised form 2 January 2020; Accepted 13 February 2020 Available online 15 February 2020 0021-9150/ © 2020 Elsevier B.V. All rights reserved.
Atherosclerosis 297 (2020) 96–101
D.-H. Cho, et al.
location of the involved arteries are different for each disease. For example, Philipp et al. reported that systemic inflammation is more relevant in PAD than in stable coronary artery disease [8]. Jang et al. reported that PAD has less relevance to obesity than CHD [9]. Although many studies on the relationship between CHD and periodontitis have been conducted, no report has described the relationship between PAD and periodontitis. The aim of this study was to determine whether the risk of PAD is high in patients with periodontitis.
periodontitis. Propensity score was calculated through a multiple logistic regression model that included the presence of periodontitis as a dependent variable and all of the variables mentioned in Table 1 as independent variables. We used greedy nearest neighbor matching on the logit of the propensity score by using calipers with a width of 0.2 of the standard deviation of the logit of the propensity score. The balance between the two matched groups was evaluated using an absolute standardized difference of < 0.1. The incidence rate of PAD was calculated by dividing the number of events by the person-years at risk. The relative hazard ratio (HR) of PAD in the patients with periodontitis compared with that in the matched control group was estimated using Cox proportional hazards model with a robust variance estimator and presented with 95% confidence intervals. Cumulative incidences of PAD in patients with periodontitis and controls were plotted using the Kaplan-Meier method. We performed a time-dependent receiver-operating characteristic (ROC) curve analysis to assess the predictive power of periodontitis and the covariates for the incidence of PAD. The ROC curves were presented at 2-year intervals since study enrollment. A p value of < 0.05 was considered statistically significant. Data were analyzed using the SAS version 9.4 software (SAS Institute, Cary, NC, USA).
2. Patients and methods 2.1. Study design and database We compared the incidence of PAD in patients with periodontitis with that in a control group. This was a retrospective matched cohort study that investigated the records of representative patients that were obtained from the Korean National Health Insurance Service-Health Screening Cohort (NHIS-HEALS) database. The entire Korean population is covered by the NHIS. However, owing to the large volume of the database and the lack of confidentiality regarding personal information available in the NHIS database, the NHIS-HEALS was modeled as a representative-sample database containing a substantial volume of representative information that does not require privacy regulations. This database included 514,832 citizens of the Republic of Korea who were between 40 and 79 years of age. This represents 10% of a random selection of all health screening participants in the index year 2002 or 2003 who were followed up until 2015. The detailed cohort protocol was described previously [10]. We obtained information on 514,832 individuals from the NHIS-HEALS database between January 1, 2003, and December 31, 2014, for our study. Of the patients diagnosed as having periodontitis during the study period, those who had been previously diagnosed as having periodontitis and those who had been diagnosed as having atherosclerotic vascular disease were excluded from the study. The control group was selected from among those who had never been diagnosed as having periodontitis during the study period and matched 1:1 to the patients with periodontitis using the propensity score matching method. Age, sex, region, insurance, body mass index (BMI), smoking history, alcohol consumption, exercise, hypertension (HTN), diabetes mellitus (DM), dyslipidemia, medication history (DM medication, HTN medication, statins, and anti-thrombotic agents), and diagnostic codes according to the International Classification of Diseases, Tenth Revision (ICD-10), were recorded. This study was approved by the ethics committee of Korea University Anam Hospital (2018AN0253). The flowchart of the study is summarized in Fig. 1.
3. Results Of the 514,832 people enrolled in the NHIS-HEALS database between January 2003 and December 2014, 72,971 patients with periodontitis were identified. The clinical characteristics of the study group and the 1:1 matched group are shown in Table 1. The prevalence of smoking in the periodontitis and matched control groups was 37.6%. The incidence rates of HTN were 21.4% and 21.7%, respectively. The incidence rates of DM were 6.1% and 5.6%, respectively; and those of dyslipidemia, 4.8% and 5.2%, respectively. The median follow-up period of the patients was 126.1 months (interquartile range, 102.2–138.2 months). During the follow-up period, 1733 patients (3.35%) developed PAD from among those with periodontitis. In the matched group, PAD occurred in 1435 patients (2.73%). The mean ages of the patients with PAD in the periodontitis and matched groups were 64.9 ± 9.4 and 66.8 ± 10.3 years, respectively. The incidence per 1000 person-years was 2.40 in the periodontitis group and 2.08 in the matched control group (Table 2). Fig. 2 shows the cumulative incidence of PAD in the periodontitis and matched control groups during the follow-up period. The HR of PAD in the periodontitis group compared with that in the matched group was 1.15 (95% confidence interval [CI], 1.07–1.23). In the time-dependent ROC curves, the areas under the curve identified every 24 months were 69.8, 71.3, 70.1, 69.9, 70.8, and 68.5, respectively (Fig. 3). Fig. 4 shows the risk of PAD associated with periodontitis exposure among the various subgroups according to the risk factors of atherosclerosis and the clinical data. In the subgroup analysis, sex, age, smoking, drinking, and HTN significantly modified the influence of periodontitis on PAD risk (p for interaction = 0.008, < 0.001, < 0.001, 0.029, and 0.007, respectively). In the periodontitis group, compared with the matched control group, male sex, young age (< 60 years), smoking, alcohol drinking, and absence of HTN, DM, and dyslipidemia were statistically significant factors in PAD incidence (HR, 95% CI: 1.27, 1.15–1.41; 1.41, 1.27–1.55; 1.48, 1.30–1.68; 1.30, 1.15–1.47; 1.25, 1.14–1.36; 1.16, 1.08–1.28; and 1.16, 1.08–1.25, respectively). BMI and regular exercise showed statistically significant effects on the incidence of PAD regardless of severity.
2.2. Definition of the clinical variables Patients from the NHIS-HEALS with ICD-10 codes K05.2–3 (periodontitis) were identified. Patients with comorbidities were defined as those with HTN (ICD-10 codes I10-13 and I15), DM (ICD-10 codes E1114), dyslipidemia (ICD-10 codes E78), ischemic heart disease (ICD-10 codes I21 and I22), stroke (ICD-10 codes I63), and PAD (ICD-10 codes I70, I70.0, I70.2–70.3, I70.8–70.9, I74.2–74.5). The definition of a current drinker was someone who drank more than once a week. Regular exercise was defined as exercise more than three times a week. To improve the accuracy of the analysis, we only included patients with at least two principal diagnostic codes for each disease. The date of disease diagnosis was used as the entry date for patients with the disease. The definition of medication use was limited to a medication prescription for more than 30 days after the time of the reference date.
4. Discussion
2.3. Statistical analyses
4.1. Mechanism of the relationship between periodontitis and PAD
Continuous variables were presented as mean (standard deviation), and categorical variables were described as numbers with percentages. Propensity score matching was performed in subjects with and without
According to recent studies, two indirect mechanisms and one direct mechanism can be assumed in the association between periodontitis and the incidence of PAD [11,12]. The first indirect mechanism is the 97
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Fig. 1. Flowchart of the study population selection. Table 1 Baseline characteristics. Variables
Periodontitis cases (n = 72,971)
Matched controls (n = 72,971)
ASD
Age (years), mean (SD) Male, n (%) Smoking, ever n (%) Current drinker, n (%) Regular exercise, n (%) Body mass index, mean (SD) Comorbidity Hypertension, n (%) Diabetes mellitus, n (%) Dyslipidemia, n (%) Medication Antidiabetics Oral hypoglycemic agents, n (%) Insulin, n (%) Antihypertensives Inhibitors of the renin-angiotensin system, n (%) Calcium channel blocker, n (%) α-Blockers, n (%) β-Blockers, n (%) Diuretics, n (%) Vasodilators, n (%) Statins, n (%)
54.9 (8.9) 40,655 (55.7) 27,435 (37.6) 29,885 (41.0) 19,677 (27.0) 23.8 (2.8)
55.1 (10.4) 40,655 (55.7) 27,435 (37.6) 30,283 (41.5) 18,806 (25.8) 23.7 (3.0)
0.011 < .001 < .001 0.011 0.027 0.036
15,635 (21.4) 4414 (6.1) 3475 (4.8)
15,814 (21.7) 4108 (5.6) 3789 (5.2)
0.006 0.018 0.020
3610 (5.0) 200 (0.3)
3253 (4.5) 173 (0.2)
0.023 0.007
4810 (6.6) 8077 (11.1) 2392 (3.3) 5391 (7.4) 6801 (9.3) 10 (0.01) 3190 (4.4)
4750 (6.5) 7918 (10.9) 2696 (3.7) 5302 (7.3) 6946 (9.5) 11 (0.02) 3435 (4.7)
0.003 0.007 0.023 0.005 0.007 0.001 0.016
ASD, absolute standardized difference. Comorbidity: disease identified more than once with the main diagnostic code by the reference date. Medication: prescribed medication for ≥30 days from the base date.
development and progression of atherosclerosis by systemic inflammation. Proinflammatory cytokines, including tumor necrosis factor-α, interleukin (IL) 1, and IL-6 induce the production of C-reactive protein and fibrinogen in the liver, which leads to atherogenesis [13,14]. In fact, anti-inflammatory treatment with canakinumab therapy in atherosclerotic disease has shown significantly lower
incidence rates of recurrent cardiovascular events corresponding to the decreased C-reactive protein levels [15]. A second indirect mechanism is the molecular mimicry theory. Molecular mimicry occurs when similarities between foreign and self-peptides produce cross activation of auto-reactive T or B cells [16]. Cross-reactive autoantibodies to periodontal bacterial lipopolysaccharides and heat shock proteins (HSP) 98
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Table 2 Relative risk of peripheral arterial disease in the patients with periodontitis compared with that in the controls.
No. of events Cumulative incidence (%) Incidence rate per 1000 person-years HR (95% CI)
Periodontitis cases (n = 72,971)
Matched controls (n = 72,971)
p
1733 3.35 2.40 1.15 (1.07–1.23)
1435 2.73 2.08 1.00
< .001
Fig. 2. Cumulative incidence of periodontitis in the patient and matched control groups between 2003 and 2014.
Fig. 3. Confounder-adjusted time-dependent ROC curves for PAD risk according to the presence of periodontitis.
99
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Fig. 4. Risk of peripheral arterial disease with or without periodontitis in the subgroups as stratified by other covariates.
have been identified [17,18]. The autoantibodies generated by bacterial lipopolysaccharides and HSP also cause an immune response to HSP 60, resulting in endothelial damage [19]. A direct mechanism in the association between periodontitis and PAD can be explained by the bacteremia caused by periodontal pathogens. In fact, bacteremia is a common daily event during chewing or tooth brushing [20]. After transient bacteremia, pathogens from a periodontal location circulate either within phagocytic cells or extracellularly and deposited in atherosclerotic lesions [21].
difference in the incidence of PAD was found between the periodontitis and control groups of female, old, non-smoking, and non-currently drinking patients. The male, young, smoking, and drinking subgroups all corresponded to the relatively poor oral hygiene conditions [22–24]. These results are probably due to the synergistic effects of poor oral hygiene and periodontitis. The association between younger age and higher risk of atherosclerotic vascular disease under the setting of periodontitis than that in older patients has a different explanation. Invasive periodontal treatment is more common in elderly patients and has the effect of lowering the risk of long-term atherosclerotic vascular disease [25,26]. Paradoxically, the incidence of PAD was found to be higher with periodontitis in the group without HTN, DM, and dyslipidemia, which are obvious risk factors of PAD. This may be because the effects of HTN, DM, and dyslipidemia, which are conventional risk factors of PAD, overwhelm the influence of periodontitis on PAD.
4.2. Effect of periodontitis on PAD risk according to patient condition A subgroup analysis revealed that the incidence of PAD was increased when periodontitis was present in male, young (< 60 years old), smoking, and currently drinking patients. However, no significant 100
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4.3. Limitations
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This study has some limitations. The diagnoses of the diseases, including periodontitis and PAD, could be inaccurate. The data used in this study were based on the physician's input of the disease name as classified according to the ICD-10. Therefore, objective data are lacking as to why the physicians in charge diagnosed any particular disease. However, the Korean NHIS routinely and randomly samples patient charts to check the accuracy of the diagnosis in all medical institutions to prevent the overcharging of medical insurance reimbursement. The database could also not provide information on other risk factors of PAD, such as family history and C-reactive protein levels. However, most of the existing nationwide studies are based on comorbidity risk factor data, including DM and HTN. The data mainly used are information obtained using ICD codes; this study includes health-related behaviors such as smoking, drinking, and exercise [27–29]. In conclusion, this study revealed that the incidence of PAD increased in the patients with periodontitis. Thus, the control of periodontitis plays an important role in the prevention of PAD, in addition to correcting conventional risk factors such as DM, HTN, dyslipidemia, and smoking. Author contributions Gwon designed the study. Choi performed the statistical analysis. Cho and Song analyzed the data and wrote the manuscript with input from all the authors. Gwon conceived the study and were in charge of the overall direction and planning. Declaration of competing interest The authors declared they do not have anything to disclose regarding conflict of interest with respect to this manuscript. References [1] R.R. Packard, P. Libby, Inflammation in atherosclerosis: from vascular biology to biomarker discovery and risk prediction, Clin. Chem. 54 (1) (2008) 24–38. [2] B.L. Pihlstrom, B.S. Michalowicz, N.W. Johnson, Periodontal diseases, Lancet 366 (9499) (2005) 1809–1820. [3] K. El Kholy, R.J. Genco, T.E. Van Dyke, Oral infections and cardiovascular disease, Trends Endocrinol. Metabol. 26 (6) (2015) 315–321. [4] G.M. Hansen, A. Egeberg, P. Holmstrup, P.R. Hansen, Relation of periodontitis to risk of cardiovascular and all-cause mortality (from a Danish Nationwide Cohort Study), Am. J. Cardiol. 118 (4) (2016) 489–493. [5] T. Senba, Y. Kobayashi, K. Inoue, C. Kaneto, M. Inoue, et al., The association between self-reported periodontitis and coronary heart disease—from MY Health up Study, J. Occup. Health 50 (3) (2008) 283–287. [6] J.D. Beck, P. Eke, G. Heiss, D. Couper, D. Lin, et al., Periodontal disease and coronary heart disease: a reappraisal of the exposure, Circulation 112 (1) (2005) 19–24. [7] J.R. Elter, C.M.E. Champagne, S. Offenbacher, J.D. Beck, Relationship of periodontal disease and tooth loss to prevalence of coronary heart disease, J. Periodontol. 75 (6) (2004) 782–790.
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