Associations Among Tooth Loss, Periodontitis, and Carotid Intima-Media Thickness: the Nagahama Study (2024)

Abstract

Aims: This study aimed to clarify the relationships among tooth loss, periodontal condition, and subclinical atherosclerosis from the aspect of intensity, extent, and duration of inflammation.

Methods: This cross-sectional study included 9,778 people from the Nagahama Study, a large-scale, general population-based study conducted in Japan. The number of teeth and periodontal status, including the attachment level (AL) and pocket depth (PD) of representative teeth from six regions, were evaluated by dentists. The maximum intima-media thickness (IMT) of the common carotid artery was used as an index of atherosclerosis.

Results: In the multivariate analysis adjusted for conventional risk factors, a large number of missing teeth (＜9 remaining teeth), which related to long-lasting inflammation indicative of the highest stage of periodontitis, was identified as an independent determinant of IMT in a general population (coefficient: 0.042; 95% confidence interval [CI]: 0.016 to 0.068). The presence of two or more regions with an AL ≥4 mm, which is indicative of the progressing, long-lasting stages of periodontal inflammation, was also independently associated with IMT (coefficient: 0.016; 95% CI: 0.004 to 0.028). On the contrary, PD, a measure of the early and reversible phases of periodontal inflammation, and loss of AL in the group without tooth loss were not significantly associated with IMT, because of the limited degree of accumulated periodontitis.

Conclusion: The present results suggest that the association between periodontitis and atherosclerosis depends on the inflammation intensity, extent, and duration.

Introduction

Atherosclerosis of large arteries is an established risk factor for cardiovascular disease^1-3). Carotid intima-media thickness (IMT) is a non-invasive representative measure of atherosclerosis and is considered a marker for the early stages of atherosclerosis²⁾. Hypertension, dyslipidemia, diabetes, and smoking are the primary causes of pathophysiological changes in the vasculature^4-6), whereas the associations between IMT and diabetes-related indicators have been inconsistent^7-9).

On the other hand, several studies of general populations^10-14) have reported that periodontal disease is an independent determinant of IMT. These findings were supported by a large-scale study of more than 6,000 individuals from the Atherosclerosis Risk in Communities Study population¹⁵⁾, which also reported a significant association between severe periodontitis and carotid IMT. In addition, a prospective study found a relationship between longitudinal improvement in clinical and microbial periodontal status and a decreased rate of carotid artery IMT progression with an average follow-up of 3 years¹⁶⁾, which supports these results. The mechanism underlying this link might be a chronic, systemic, low-grade inflammatory response related to inflamed oral tissues^14-18).

In our previous report using a dataset from the first investigation of the Nagahama Study, we confirmed that the number of missing teeth, which is a proxy for the accumulated burden of periodontitis, was positively associated with inflammatory markers, such as serum high-sensitivity C-reactive protein (hs-CRP) levels¹⁹⁾. Periodontal disease induces chronic low-grade inflammation that eventually damages dental support tissues and progresses to tooth loss²⁰⁾. Therefore, we hypothesized that as the duration, extent, and intensity of periodontitis increase, its effect on atherosclerosis may gradually increase. Furthermore, given that the degree of inflammation in patients with current periodontitis partly depends on the number of teeth, namely, the surface area and depth of inflamed periodontal tissue that is directly involved in inflammation, the number of existing teeth may influence the relationship between periodontitis and atherosclerosis. However, to date, no large study has evaluated these relationships in detail from the perspective of the degree of accumulated periodontal inflammation.

Thus, we aimed to investigate the relationships among the degree of current periodontitis, tooth loss, which represents the accumulation of long-lasting inflammation indicative of the highest stage of periodontitis²⁰⁾, and maximum IMT of the common carotid artery²¹⁾ as an index of atherosclerosis in a cohort of the general Japanese population.

Methods

Study Participants

We analyzed a dataset from the second investigation of the Nagahama study^{22, 23)}, a prospective cohort study of community-dwelling residents in Nagahama, a rural city with 125,000 inhabitants located in central Japan. We recruited study participants from the baseline investigation performed between 2008 and 2010 among Nagahama residents aged 30–74 years who were living independently without physical impairment or dysfunction. From the baseline population of 9,764 individuals, we included 8,289 who participated in a second investigation five years later together with 1,561 newly recruited participants who met the study criteria, for a total population for the second investigation of 9,850 participants. Finally, 9,778 participants were included in the cross-sectional analysis after excluding 72 individuals who met any of the following criteria: pregnancy (considering the temporary exacerbation of gingivitis due to fluctuations in female hormones) (n=9), pacemaker implantation (because the etiology that necessitated this treatment is unknown) (n=12), undergoing hemodialysis therapy (n=5), or in severe renal functional decline (estimated glomerular filtration rate [eGFR] ＜30 mL/min/1.73 m²; n=16) (considering another pathway may influence a progression of atherosclerosis, specifically, decreased renal function is associated with an accelerated increase in carotid IMT²⁴⁾), and lacking of information on the dental (n=12) or clinical (n=18) parameters.

All study procedures were conducted according to the principles of the Declaration of Helsinki and were approved by the ethics committee of the Kyoto University Graduate School of Medicine and Nagahama Municipal Review Board. Written informed consent was obtained from all participants.

Dental Parameters

The number of teeth, attachment level (AL), and pocket depth (PD) were evaluated by calibrated dentists at the Department of Oral and Maxillofacial Surgery. Healthy, carious, and treated teeth, including crown, inlay, and abutment teeth for prostheses, were included in the number of teeth, whereas third molars were excluded from the count of the number of teeth because they tended to be completely impacted or congenitally missing. To determine tooth loss owing to infections, patients were excluded if they had: tooth loss due to infections such as periodontitis or dental caries by oral bacteria, tooth loss due to extraction for orthodontic treatment, congenitally missing teeth, or impacted teeth using information from clinical interviews. AL was defined as the distance (in millimeters) from the cementoenamel junction to the base of the pocket sulcus. PD was defined as the distance from the free gingival margin to the base of the pocket sulcus. AL and PD were assessed in the representative teeth in each of the six regions (dental formula; upper right, 14–18; upper middle, 13–23; upper left, 24–28; lower left, 34–38; lower middle, 33–43; and lower right, 44–48). Measurements were taken at six sites per tooth (mesiobuccal, midbuccal, distobuccal, mesiolingual, midlingual, and distolingual) using a conventional method (World Health Organization Oral Health Surveys Basic Methods 4^th Edition, 1997) with a World Health Organization probe. The number of regions (ranging from 0–6) in which the maximum AL or PD of the representative tooth was more than 4 mm was used in the analyses as indices of AL and PD. In this calculation, the edentulous regions were considered normal regions.

Carotid IMT Measurement

Atherosclerosis of large arteries was assessed by maximum IMT of the common carotid artery²⁵⁾. IMT was measured after the patient rested for a few minutes in the supine position using one of the following devices with a 7.5 MHz probe: Prosound 2 or SSD-3500SV (Aloka Co., Ltd., Tokyo, Japan), XARIO SSA-660A (Toshiba Medical Systems Corporation, Tochigi, Japan), or UF-760AG (f*ckuda Denshi Co., Ltd., Tokyo, Japan). The IMT of the far wall was manually (using the Aloka or Toshiba device) or automatically (f*ckuda Denshi device) measured from B-mode images at 1-cm intervals, proximal to the bulb using the lateral approach. For the analysis, the maximum IMT was manually calculated from three readings or automatically measured from 272 readings within a 2-cm range.

Basic Clinical Parameters

The basic clinical parameters used in this study were obtained from personal health records created during the second investigation. Blood pressure (BP) was measured twice after patients rested for a few minutes in a seated position using a standard automatic cuff-oscillometric device (HEM-9000AI, Omron Healthcare, Kyoto, Japan); the mean of the two readings was used for analysis. Hypertension was defined as a systolic BP ≥140 mmHg, diastolic BP ≥90 mmHg, or the use of antihypertensive drugs. Renal function was assessed by calculating the eGFR using the following formula: 194×(creatinine value)^−1.094×(age)^−0.287 (×0.739 if female)²⁶⁾. Medication use and smoking habits were assessed using a structured questionnaire. The Brinkman index was calculated by multiplying the number of cigarettes smoked per day by the number of years the person smoked.

Statistical Analyses

Values are represented as the mean±standard deviation or frequency, or median (interquartile range). Group differences in numeric variables were assessed using analysis of variance. The chi-square test was used for categorical variables. Factors independently associated with maximum IMT were assessed by multivariate linear regression analysis adjusted for age, sex, body mass index, current or past smoking, Brinkman index, systolic blood pressure, and hemoglobin A1c, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, and triglyceride levels. Statistical analyses were performed using JMP Pro 14.3.0 software (SAS Institute Inc., Cary, NC, USA). Trend test was performed by a Jonckheere-Terpstra method using R software (https://www.r-project.org) with PMCMRplus package. P values ＜0.05 were considered statistically significant. In this study, we followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement guidelines for the analysis of observational data.

Results

The clinical characteristics of the study participants are summarized in Table 1. In a simple comparison, age (r=0.462), male sex (men, 0.92±0.37; women, 0.80±0.23 mm), body mass index (r=0.165), current smoking status (smoker, 0.88±0.36; never or past smoker, 0.82±0.24 mm), systolic BP (r=0.332), hemoglobin A1c level (r=0.219), and hs-CRP (r=0.160) were positively associated with maximum IMT (all P＜0.001).

The number of teeth (Fig.1A, Supplementary Fig.1) showed a reverse association with maximum IMT. The number of regions where the AL (Fig.1B, Supplementary Fig.2A) or PD (Fig.1C, Supplementary Fig.2B) was ≥4 mm, was positively correlated with the maximum IMT. In this analysis, we arbitrarily categorized the participants into six (Fig.1A) or three (Fig.1B and 1C) groups by considering the number of participants in each detailed subgroup (Supplementary Figs.1 and 2). Given that tooth loss and worse periodontal status shared several risk factors with increasing maximum IMT (Supplementary Tables 1 and 2), we performed a multiple linear regression analysis to identify factors independently associated with maximum IMT (Table 2). The results of the regression analysis showed that having ＜9 teeth was an independent determinant of maximum IMT (coefficient: 0.042; 95% confidence interval [CI]: 0.016 to 0.068; reference, having 28 teeth). A worse AL was also independently associated with maximum IMT, whereas no significant association was observed between PD and maximum IMT. Full results of the regression analysis are presented in Supplementary Table 3.

As the number of teeth may influence the relationship between AL and maximum IMT, we performed a subgroup analysis based on the number of teeth (Fig.2). The results of the covariate-adjusted analysis indicated that having more than two regions with AL ≥4 mm was associated with maximum IMT only in the subgroup with 25–27 teeth (coefficient: 0.036; [CI]: 0.018 to 0.055; reference, no region with AL ≥4 mm). Similar results were observed in the sensitivity analyses, which included participants with measurable AL in all six regions (Supplementary Fig.3).

Discussion

In this cross-sectional analysis of a large general population, we found that a large number of missing teeth (＜9 remaining teeth), as well as loss of AL with moderate tooth loss, were independently associated with subclinical atherosclerosis of a large artery from major risk factors in a general population. In contrast, PD and AL in subjects with a complete set of teeth or high tooth loss were not associated with maximum IMT.

In the univariate analysis, there was a linear inverse correlation between the number of teeth and maximum IMT. The presence of ＜9 remaining teeth was identified as an independent determinant for increased maximum IMT after adjusting for possible covariates. Because periodontal disease is a major reason for tooth extraction in middle-aged and older Japanese individuals²⁷⁾, these results suggest that the most persistent and severe stage of periodontitis is associated with atherosclerosis. A similar situation exists for the AL. The AL is more indicative of advanced, long-lasting stages of periodontal inflammation than the current burden of oral infection^{28, 29)}. Our results are similar to those of several previous studies, which suggest that severe periodontitis is associated with carotid plaque formation or an increase in carotid IMT¹⁴⁾. Meanwhile, we did not find a significant association between maximum IMT and PD, a measure of the early and reversible phases of periodontal inflammation²⁹⁾. In contrast, a previous cross-sectional study found a weak association between these variables, although a direct comparison between studies was difficult because the mean PD was used as a representative index¹⁰⁾.

In the analyses considering both AL and the number of teeth, the association between AL and maximum IMT was prominent in participants who had lost 1–3 teeth. AL may be a useful marker of periodontal disease especially in a population of people that have many teeth with periodontal disease remaining in the oral cavity. In contrast, AL was not associated with the maximum IMT in individuals with a complete set of teeth. If periodontal inflammation is present, although not of sufficient intensity and duration to cause tooth loss, periodontitis of the present teeth may represent the limited inflammatory effect of actual atherosclerotic changes. In contrast, in participants with 4–28 missing teeth, AL was not associated with maximum IMT, even when the analysis was limited to participants with measurable AL in all six regions in the sensitivity analyses. The deleterious effect of periodontal inflammation in the remaining teeth on atherosclerosis may be underestimated in patients that already have a large number of missing teeth. When one loses teeth previously affected by periodontal disease, evidence of the cumulative effect of periodontitis is removed, and systemic damage may partly persist¹⁷⁾. The observation that participants with edentulism (loss of all teeth) showed incident hypertension and the highest cardiovascular disease mortality, heart failure, stroke, and all-cause death rates despite the absence of current periodontal inflammation supports this hypothesis^30-33). Therefore, we speculated that long-term periodontal inflammation in the past has a stronger adverse effect on cardiovascular diseases, including atherosclerosis, than current periodontal disease. The inflammation intensity, extent, and duration should be considered in systemic inflammation. In future studies that consider the influence of periodontal inflammation on atherosclerosis, we suggest that it may be better to consider the current periodontal status as well as the number of missing teeth, which is indicative of the long-term cumulative effects of concurrent periodontal disease, and to judge the results in a comprehensive manner. The results of the present study are interesting from a hypothesis-generating perspective; however, further studies with whole teeth examination are required to verify our results.

We previously reported that tooth loss was associated with arterial wall stiffness, assessed using the cardio-ankle vascular index²²⁾, which is an index of arterial stiffness calculated from the pulse wave velocity of a large artery. Loss of elasticity in the media of arterial walls due to elastin degradation and collagen formation is a major cause of arterial stiffness, while lipid accumulation and consequent vascular inflammation are the pathophysiological basis of atherosclerosis, as assessed by carotid IMT³⁴⁾. Systemic inflammation is associated not only with atherosclerosis but also arterial wall stiffness³⁵⁾. Systemic inflammation may be a factor underlying the relationship between tooth loss and pathophysiological changes in large arteries.

Many studies have suggested that periodontitis is associated with hypertension^{29, 32, 36-38)}. Proinflammatory cytokines may lead to endothelial dysfunction by influencing endothelial cells, decreasing local availability of endothelium-derived relaxing factor (i.e., nitric oxide [NO]), which relaxes vascular vessels^{37, 39)}. Periodontal inflammation may also cause perivascular adipose tissue inflammation, which leads to endothelial dysfunction with NO bioavailability loss, contributing to hypertension and atherosclerosis^{37, 38, 40)}. In the multivariate analysis in the present study, although there was a close correlation between BP and maximum IMT, the association between periodontitis and maximum IMT was independent of BP (Supplementary Table 3). These results suggest the possibility that hypertension may sometimes occur because of pathophysiological changes in large arteries due to inflammation from periodontal disease. Nevertheless, since this was a cross-sectional study, longitudinal studies are required to clarify the mechanisms underlying these associations.

A major strength of this study was the large population size, which enabled subgroup analyses based on the number of teeth. A major limitation of this study was the use of AL and PD in six representative teeth as an index of periodontitis. The association between periodontitis severity and IMT may be more precisely evaluated using the AL and PD of all remaining teeth. Furthermore, we recognized the limitation of the lack of information regarding the reasons for tooth loss, which is the case in many cohort studies. Although untreated severe dental caries can also cause systemic inflammation by oral bacteria, we could not exclude tooth loss resulting from dental caries from the number of missing teeth. We also recognized that increased tooth loss often leads to decreased maximum bite force and masticatory performance which results in poor nutritional intake⁴¹⁾, deterioration of nutritional balance, or overnutrition, which may contribute to increased incidences of atherosclerotic cardiovascular diseases and metabolic syndrome^{6, 42, 43)}. However, we did not evaluate the effect of masticatory performance on IMT in this study. In addition, this was a cross-sectional study, which, although robust, prevents us from ruling out the possibility of reverse causality. Our study used questionnaire-based data; hence, there was a possibility of self-reporting bias. Furthermore, because the population of this study was community dwellers in a limited area of Japan, the generalizability of the present findings to other populations may be limited.

Conclusion

This study showed that a large number of missing teeth (＜9 remaining teeth), as well as loss of AL with moderate tooth loss, was associated with subclinical atherosclerosis of large arteries in a general population. In contrast, PD, and AL in subjects with a complete set of teeth or with high teeth loss were not associated with maximum IMT. The present results suggest that intensity, extent, and duration of inflammation may be involved in the association between periodontitis and atherosclerosis.

Appendix

The Nagahama Study Group Executive Committee is comprised of the following individuals: Yasuharu Tabara, Takahisa Kawaguchi, Kazuya Setoh, Yoshimitsu Takahashi, Shinji Kosugi, Takeo Nakayama, and Fumihiko Matsuda from the Center for Genomic Medicine, Kyoto University Graduate School of Medicine (YaT, TK, KS, FM); Department of Health Informatics (YoT, TN); Department of Medical Ethics and Medical Genetics (SK); and Kyoto University School of Public Health.

Acknowledgments

We are extremely grateful to the Nagahama City Office and the nonprofit organization Zeroji Club for their assistance with the Nagahama study. We also thank Dr. Takahisa Kawaguchi and Dr. Asumi Mori for data acquisition. We also thank Editage for English language editing.

Declaration of Conflict of Interest According to ICMJE Form

SF, TW, TY, SY, KN, KA, MK, AY, CU, KS, YT, FM, KB have no conflicts of interest to declare. TN reports personal fees from Pfizer Japan Inc., MSD K.K., Ohtsuka Pharmaceutical Co., Chugai Pharmaceutical Co., Dentsu Co., Takeda Pharmaceutical Co., Janssen Pharmaceutical K.K., Boehringer Ingelheim International GmbH, Eli Lilly Japan K.K., Baxter, Alexion, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma K.K., Allergan Japan K.K., and Maruho Co., Ltd.; and research grants from HANSHIN Dispensing Holding Co., Ltd., Nakagawa Pharmacy Co., Ltd., and Konica Minolta, Inc., all of which were outside the submitted work.

Author Contributions

Shizuko f*ckuhara: conception, design, data acquisition and interpretation, statistical analyses, and drafting the manuscript

Takuma Watanabe: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Toru Yamazaki: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Shigeki Yamanaka: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Kazumasa Nakao: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Keita Asai: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Marina Kashiwagi: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Atsue Yamazaki: data interpretation, and critical revision of the manuscript

Chisa Umebachi: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Kazuya Setoh: conception, design, data acquisition and interpretation, statistical analyses, and critical revision of the manuscript

Yasuharu Tabara: conception, design, data acquisition and interpretation, statistical analyses, and drafting the manuscript

Takeo Nakayama: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Fumihiko Matsuda: conception, design, data acquisition and interpretation, and critical revision of the manuscript

Kazuhisa Bessho: conception, design, data interpretation, and critical revision of the manuscript

All authors approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Funding

The work was supported by university grants from the Center of Innovation Program, Global University Project, and Grants-in-Aid for Scientific Research (grant numbers 25293141, 26670313, 26293198, 17H04182, 17H04126, 17H04123, 18K18450, 19K19312, and 22K10339); Ministry of Education, Culture, Sports, Science and Technology of Japan; Practical Research Project for Rare/Intractable Diseases (grant numbers ek0109070, ek0109196, and ek0109348), Comprehensive Research on Aging and Health Science Research Grants for Dementia R&D (grant numbers dk0207006 and dk0207027), Program for an Integrated Database of Clinical and Genomic Information (grant number kk0205008); Practical Research Project for Lifestyle-related Diseases including Cardiovascular Diseases and Diabetes Mellitus (grant numbers ek0210066, ek0210096, and ek0210116); Research Program for Health Behavior Modification by Utilizing IoT (grant number le0110005) from the Japan Agency for Medical Research and Development (AMED); Welfare Sciences Research Grants; Research on Region Medical from the Ministry of Health, Labor and Welfare of Japan; Takeda Medical Research Foundation; Mitsubishi Foundation; Daiwa Securities Health Foundation; Sumitomo Foundation; Smoking Research Foundation; and 8020 Promotion Foundation.

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