Abstract
Introduction:
Streptococcus mutans is a known cause of dental caries that contains a collagen-binding protein, Cnm, and exhibits inhibition of platelet aggregation and matrix metalloproteinase-9 activation. This strain has been linked to aggravation of experimental intracerebral hemorrhage (ICH) and may be a risk factor for ICH.The purpose of this study was to test the association between dental caries and incident ICH.
Methods:
Presence of dental caries and periodontal disease was assessed in subjects from the Dental Atherosclerosis Risk in Communities Study (DARIC) without prior stroke or ICH. This cohort was followed for incident ICH over a period of 10 years. Cox regression was used to compute crude and adjusted hazards ratio from the dental assessment.
Results:
Among 6,315 subjects, dental surface caries and/or root caries were recorded in 1338 (27%) subjects. Of those 7 (0.5%) had incident ICH over a period of 10 years following the visit 4 assessment. Of the remaining 4977 subjects, 10 (0.2%) had incident ICH. Those with dental caries versus those without dental caries were younger (mean age 60±6 vs. 59±6, p<0.001), had a greater proportion of males (51% vs. 44%, p<0.001), African Americans (44% vs 10%, p<0.001) and were hypertensive (42% vs. 31%, p<0.001). The association between caries and ICH was significant (crude HR 2.69, 95% CI 1.02–7.06) and strengthened after adjustment for age, gender, race, education level, hypertension and periodontal disease (adj. HR 3.88, 95% CI 1.34–11.24).
Discussion/Conclusion:
Dental caries is a potential risk for incident ICH after caries detection. Future studies are needed to determine if treatment of dental caries can reduce the risk of ICH.
Keywords: Intracerebral hemorrhage, dental caries, infection
INTRODUCTION
Stroke is one of the leading causes of morbidity and mortality in the United States [1, 2]. Stroke can be classified into ischemic or hemorrhagic subtypes, with intracerebral hemorrhage (ICH) being the most common type of hemorrhagic stroke [3]. ICH patients have the highest morbidity and mortality among major stroke patients [4]. Hypertension, age, anticoagulant use, and alcohol use are known risk factors for ICH [5, 4], but one third of all ICH cases have yet to be attributed to any particular risk factor [6].
Dental infection, including caries and periodontal disease, is a known promoter of atherosclerotic cardiovascular disease through systemic inflammation, molecular mimicry, and bacteremia [7]. Poor oral health is a known risk factor for cerebrovascular disease [8], especially ischemic stroke [9, 10], but there is limited information available about dental caries and ICH.
Dental caries is formed by acid-fermenting oral bacteria that break down dietary carbohydrates to form acidic byproducts that subsequently destroy dental hard tissue [11]. Bacterial infection, specifically implicated in periodontal disease, is known to be associated with cardiovascular diseases [12]. Streptococcus mutans is a known bacterial cause of dental caries that contains a collagen-binding protein, Cnm, and demonstrates inhibition of platelet aggregation and matrix metalloproteinase-9 activation. This strain has been linked to aggravation of ICH in mice and thus may be a risk factor for ICH [13].
This is one of the first clinical-epidemiological studies to evaluate the association between dental caries and incident ICH.
MATERIALS AND METHODS
Study Population: The Atherosclerosis Risk in Communities (ARIC) Study was created to examine the causes of atherosclerosis and its associated clinical outcomes [14]. The study enrolled 15,792 participants aged 45–64 at baseline from 4 communities: Forsyth County, NC, Washington County, MD, the northwest suburbs of Minneapolis, MN, and Jackson, MS (African American participants only). ARIC began enrolling participants in 1987, and the initial baseline visits were conducted from 1987–1989. In-person follow-up took place at the following intervals: visit 2 (1990–1992), visit 3 (1993–1995), visit 4 (1996–1998), visit 5 (2011–2013), visit 6 (2016–2017), visit 7 (2018–2019), visit 8 (2020), and visit 9 beginning in June 2021.
Vascular risk factors were examined, and hospital medical records were obtained, particularly if hospitalizations occurred. The ARIC Investigators are willing to share the data used in this article with a researcher for the purposes of reproducing the results, subject to completion of a data use agreement ensuring appropriate protection of the confidentiality of ARIC participants’ data. The institutional review board of all participating institutions approved the study and all subjects provided informed consent to participate.
Dental ARIC, an ancillary study of ARIC, was conducted at the fourth clinic visit. During this visit, a dental examination was performed. Data collection included a comprehensive dental examination, questionnaire, and sample collection. This cohort was followed for a period of incident ICH using follow-up calls, hospital discharge diagnosis codes, and death certificates for the initial 10 years. Dentate participants agreeing to a dental exam were included. Participants with medical contraindications to dental exams, those with dental implants only, and individuals who were not African American or white (due to limited sample size of other races) were excluded. Participants with a prior history of stroke and/or ICH were also excluded.
Assessment of dental caries
Dentate participants agreeing to a dental examination underwent full mouth assessments at visit 4. Participants were assessed for cavitations, which were defined as teeth with a discontinuity of the enamel surface caused by the loss of tooth substance. For each tooth, a numerical status was recorded denoting whether a tooth was sound, decayed or filled, missing, restored with crown, a decayed root fragment, a sound root fragment, or an implant. If the tooth status was a 2 (decayed or filled) or 4 (restored with crown), it could be coded as dental surface caries and/or dental root caries. Root caries was recorded as present if there was a discrete, well-defined, and discolored cavitation on the root surface and the explorer entered the cavitation easily. Root caries was scored if at least half of the lesion or restoration extends apical to the cementoenamel junction. Fractures, erosion, and abrasions were considered distinct and were not recorded as caries. Patients with lesions but not frank caries were further investigated to detect pit, fissure, and smooth surface lesions as well as root and coronal caries.
Assessment of ICH
ICH diagnoses were based on computer derived diagnosis and physician medical record review, with differences adjudicated by a second physician reviewer. Classification of ICH required evidence of sudden or rapid onset of neurological symptoms lasting >24 hours or leading to death, plus demonstration of at least definite intracerebral hematoma by CT or MRI and/ordemonstration at autopsy or surgery of ICH.
Other Variables of Interest
Age, gender, race (categorized as European-American or African American), alcohol use, and smoking status at visit 4 were assessed by self-report. Hypertension was defined as a systolic blood pressure of 140mmHg or higher, a diastolic blood pressure higher than 90mmHg, or use of medications to treat hypertension. Diabetes was determined by a self-reported history of a physician diagnosis of diabetes, a non-fasting blood glucose level of 200 mg/dL or higher, a fasting blood glucose level of 126mg/dL or higher, or the use of insulin or other oral hypoglycemic medications. Socioeconomic status was measured by using education status as proxy. Patients reported their education status as one of three categories: grade 12 or GED, 1–4 years of college, or graduate or professional school. Additionally, we were able to gather medication data that may contribute to ICH such as antiplatelet therapy (example daily Aspirin) and oral anticoagulation (example Warfarin).
Statistical Analysis
The cohort consisted of 6,315 participants assessed for dental caries at visit 4. Demographics and covariates including age, sex, race, body mass index, hypertension, diabetes, education, smoking status, alcohol use, and cholesterol were assessed using t-test for continuous variables and χ2 test for categorical variables. Triglycerides and serum CRP are not normally distributed and were assessed using the Mann-Whitney U test. A log rank test was run to determine differences in the time-to-event distribution for incident ICH between the dental caries and no dental caries groups. We first tested the proportional hazards assumption by including time dependent covariate in the Cox regression model. Subsequently we used Cox proportional hazards models to assess crude and adjusted hazard ratios (HRs) and 95% confidence intervals of incident ICH for initial 10 years from the dental assessment. The association between dental caries and ICH was adjusted for age, gender, race, education level, hypertension and periodontal disease. . Since all-cause mortality would be a competing risk for both CHD event and ischemic stroke, as part of primary analysis we used the Fine and Gray method to estimate multivariable adjusted subdistribution relative hazards of ischemic stroke and CHD event respectively, while adjusting for the same covariates as listed above[15].Our data may have unmeasured confounders. A concern may be that such factors may confound the established effects of caries on outcome. As such, we assessed the sensitivity of the caries results in fitted survival models to the unmeasured confounders. All data analyses for this study were conducted using SAS version 9.4 (SAS Institute, Cary, NC).
RESULTS
Of 6,315 participants assessed at visit 4 without prior ICH, 17 were found to have incident ICH over a period of 10 years. Table 1 describes the baseline characteristics of the population with dental caries versus no dental caries. Dental caries was found in 1338 participants (27%) of the cohort. Participants with dental caries had a significantly higher proportion of males, African Americans, and current smokers. Participants with dental caries also had significantly higher mean BMI, LDL cholesterol, and higher median triglycerides as well as serum CRP levels. The cohort with caries had significantly higher incidence of hypertension and diabetes as compared to those without dental caries. People with dental caries were significantly more likely to have a lower education level and were less likely to be current or former alcohol users. There was a noted higher proportion of antiplatelet therapy in the no-caries group, and no significant difference in oral anticoagulation use between the caries and no-caries groups, suggestive that they are unlikely to contribute to the ICH.
Table 1.
Baseline characteristics of the study participants according to presence of dental surface and/or root caries in the Atherosclerosis Risk in Communities (ARIC) Study
| Dental surface and/or root caries | |||
|---|---|---|---|
| Absent (n=5006) | Present (n=1345) | p-value | |
| Age (yr) | 60±6 | 59±6 | <.001 |
| Sex (%) | |||
| Female | 56.3% | 48.8% | <.001 |
| Male | 43.7% | 51.2% | |
| Race (%) | |||
| African American | 9.6% | 44.1% | <.001 |
| White | 90.4% | 55.9% | |
| Body Mass Index* | 27.4±5.7 | 28.95±6.6 | <.001 |
| Hypertension (%) | 31.1% | 41.9% | <.001 |
| Diabetes (%) | 11.7% | 18.7% | <.001 |
| Education (%) | |||
| Grade 12 or GED | 8.7% | 27.5% | <.001 |
| 1–4 years college | 44.1% | 39.7% | |
| Graduate or professional school | 47.3% | 32.8% | |
| Smoking (%) | |||
| Never | 47.7% | 46.7% | <.001 |
| Former | 41.5% | 36.7% | |
| Current | 10.8% | 16.6% | |
| Alcohol (%) | |||
| Never | 16.8% | 28.5% | <.001 |
| Former | 24.5% | 32.6% | |
| Current | 58.7% | 39.0% | |
| Cholesterol (mg/dL) | |||
| LDL† | 122±32 | 124±35 | .04 |
| HDL† | 51±17 | 50±16 | .013 |
| Triglycerides (mg/dL)‡ | 125 (89, 174) | 112 (82, 165) | <.001 |
| High sensitivity CRP (mg/dL)‡ | 2.6 (0.9, 6.8) | 3.3 (1.2, 7.6) | <.001 |
| Medications Antiplatelet therapy Anticoagulant therapy |
33% 7% |
27% 10% |
<0.001 0.316 |
BMI (body mass index) is the weight in kilograms divided by the square of the height in meters
Entries are mean ± SD
Entries are median (25th percentile, 75th percentile)
On introduction of time-dependent covariate in the Cox regression analysis, it showed a nonsignificant result (p=0.661) suggestive that the proportional hazards assumption was met. During a follow-up period of 10 years, incident ICH was noted in 7 (0.5%) out of 1,338 participants with dental caries and 10 (0.2%) out of 4,967 participants without dental caries. The dental caries-ICH association is depicted in a standard Kaplan-Meier survival curve in Figure 1, representing time-to-hemorrhage stratified by dental caries versus no dental caries. There was no significant difference in overall ICH free survival log-rank testing p=0.04. Univariable and multivariate Cox regression analyses were performed to calculate the crude and adjusted HR, respectively. Adjusted HR included adjustments for age, gender, race, education level, and hypertension. Association between dental caries and incident ICH after dental caries assessment at visit 4 was significant (crude HR 2.69; 95% CI 1.02–7.06, p=0.05). Dental caries-ICH association remained significant after adjusting for age, gender, race, education level, hypertension and periodontal disease (adj. HR 3.88, 95% CI 1.34–11.24, p=0.013). The sensitivity of the caries results in fitted survival models to the unmeasured confounder is shown in table 2. To fully mediate the association of caries, such confounders must have an HR of greater than 1.5 to result in non-significant association between caries and ICH.
Fig. 1:
Time to ICH depicted by Kaplan-Meier survival curve with Cox regression crude and adjusted HR according to presence of dental caries. Adjusted for age, gender, race, hypertension, education level and periodontal disease status.
Table 2.
Sensitivity analysis of dental caries-ICH association for binary residual confounder in adjusted model
| Residual confounding HR | Caries HR | 95% CI for Caries HR | |
|---|---|---|---|
| 1.0 | 3.88 | 1.34 | 11.24 |
| 1.1 | 3.62 | 1.25 | 10.48 |
| 1.2 | 3.40 | 1.17 | 9.85 |
| 1.3 | 3.22 | 1.11 | 9.31 |
| 1.4 | 3.06 | 1.06 | 8.86 |
| 1.5 | 2.92 | 1.01 | 8.46 |
| 1.6 | 2.80 | 0.97 | 8.11 |
| 1.7 | 2.69 | 0.93 | 7.80 |
| 1.8 | 2.60 | 0.90 | 7.53 |
| 1.9 | 2.52 | 0.87 | 7.29 |
| 2.0 | 2.44 | 0.84 | 7.07 |
Since all-cause mortality would be a competing risk for ICH, in model 2, we report a Fine and Gray Subdistribution HR that included death as an additional event type, adjusting for the same covariates as listed above. Dental caries was significantly associated with ICH (adjusted HR 1.31 95% CI 1.07–1.61).
DISCUSSION/CONCLUSION
Dental caries is a common chronic disease associated with microbiological biofilm formation. It is reversible in its early stages but can progress until the tooth is destroyed. It is the most common cause of oral pain and tooth loss, and typically progresses slowly [11]. The link between Streptococcus mutans (Sm) and dental caries is well established. Sm is one of the most well-known oral species of bacteria and is known to accelerate tooth decay [16]. In one study, Sm without collagen binding activity was found in the saliva of 58% of healthy subjects and 96% of subjects with dental caries [17]. Though Sm with collagen binding activity is typically found in only 8–10% of healthy subjects [18], Sm with collagen binding activity was found in 31% of subjects with cerebral microbleeds [19], and approximately 30% of cerebral hemorrhage patients [6]. Therefore, dental caries, often caused by Sm, may predispose individuals to incident ICH due to inflammatory burden and higher incidence of Sm serotypes containing a collagen binding protein.
Overall, we report an independent association between dental caries and incident ICH. Dental caries is prevalent among adults worldwide and is an important public health problem due to its known association with cardiovascular disease [16], cerebrovascular disease, and diabetes mellitus [8]. There are many known risk factors for dental caries. Physical risk factors include inadequate salivary flow, and high numbers of cariogenic bacteria. Lifestyle factors include poor oral hygiene and socioeconomic status [11]. Our findings suggest an association between dental caries and incident ICH, and therefore reducing risk factors for dental caries could also potentially mitigate the risk of incident ICH.
Previous studies have shown that presence of Sm is linked to shorter time to developing caries, and Cnm-positive Sm is known to promote ICH by directly inhibiting platelet aggregation [6, 19, 20]. Due to this relationship between time to development of caries with the presence of Sm and ICH promotion by this bacteria, a shorter time period of 10 years was chosen to select for cases in which Sm caused caries was implicated in ICH occurrence.
There were a few noteworthy limitations in our study. We are using presence of dental caries as a proxy for presence of Sm rather than measuring Sm in saliva directly since other studies have shown the strength of this association previously [16]. Other limitations include that the dental health variables measured at visit 4 may have changed over time. Caries was not measured at a later point in the ARIC study, therefore changes from baseline dental health were not accounted for [3]. In addition, this study used a binary assessment of caries as present (to include decayed, filled, or crowned teeth) or not present rather than employing the decayed-missing-filled teeth index as three discrete variables. It appears that the incidence of intracerebral hemorrhage in the study population is extremely low, 17 out of 6315 had hemorrhage over 10 years. This translates to incidence rate of 26.9 per 100,000 person years. A recent meta-analysis found the rate to be 29.9 per 100,000 person years (95% CI: 26.5–33.3), which is comparable to our data set [20].
ICH stroke subtype and hemorrhage location were also not assessed in these studies, which prevents the examination of possible associations between ICH subtypes and potential risk factors [3]. Our results also had a wide confidence interval. This could be due to small numbers of incident ICH, though our data are from the largest population-based longitudinal study with over 20 years of follow-up data to assess both dental caries and incident ICH. As a result we were also not able to assess a dose response of caries with ICH. Limitations also include residual and unmeasured confounding that might be present despite trying to account for this in the statistical analysis. To address confounding, we conducted a sensitivity analysis to test its effect on the association between caries and ischemic stroke. To fully mediate the association of caries, the unmeasured confounder must have an HR of greater than 1.5, a less likely scenario. Both caries and ICH are a marker of poor health status and blood pressure control. We did not have the means to capture the information at the time of hospitalization and hence this would be recognized as a possible unmeasured confounder.
Despite these limitations, the strength of this study includes its large community-based cohort, long follow-up duration, and assessment of several covariates that could have confounded the study results. Our results, combined with that of prior studies, suggest that dental caries may be a risk factor for incident cerebral hemorrhage, at least ≤10 years following their measurement, and we believe it one of the first epidemiological studies to assess this association. Although the ideal setting to test whether dental caries is associated with ICH is a randomized controlled trial (RCT), RCTs are limited in testing hypotheses with such long-term outcomes. It is known dental caries can progress slowly, and in our study we noted caries affected outcomes up to 10 years after exposure [11]. A randomized controlled trial may help ascertain if dental caries patients can benefit from regular dental cleaning and other risk factor reduction strategies to reduce ICH, resulting in a new ICH prevention strategy. However, this would need to be a prolonged study lasing for decades.
In conclusion, surface and/or root dental caries is associated with incident ICH ≤10 years after detection. This will be one of the first clinical-epidemiological study to evaluate the association between dental caries and incident ICH, and future studies are needed to validate these findings.
Sources of funding:
The Atherosclerosis Risk in Communities study has been funded in whole or in part with Federal funds from the National Heart, Lung, and Blood Institute, National Institutes of Health, Department of Health and Human Services, under Contract nos. (HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700005I, HHSN268201700004I).
The authors thank the staff and participants of the ARIC study for their important contributions. Souvik Sen MD is the PI on 1 R01 MD009738 PeRiodontal treatment to Eliminate Minority InEquality and Rural disparities in Stroke (PREMIERS) supported by National Institute of Minority Health Disparity.
Dr. Gottesman is supported by the NINDS Intramural Research Program.
Footnotes
STATEMENTS
The institutional review boards of all participating institutions approved the study and all participants provided written informed consent.
Ethics
The ethical (institutional) review boards of all ARIC Study field centers participating institutions (the Universities of Mississippi, Minnesota, and North Carolina, Wake Forest University, and Johns Hopkins University) and the coordinating center (University of North Carolina) reviewed and approved the Atherosclerosis Risk In Communities (ARIC) study and its protocols. The MRI study was approved by the institutional review boards at each site (protocol name: The Intracranial Atherosclerotic Disease and Cognitive Impairment Study). All participants provided written informed consent. The research was conducted in accordance with the principles described in the Declaration of Helsinki.
Conflict(s)-of-Interest/Disclosure(s):
The authors have no conflicts of interest to declare.
Data Availability:
The ARIC Investigators are willing to share the data used in this article with a researcher for the purposes of reproducing the results, subject to completion of a data use agreement ensuring appropriate protection of the confidentiality of ARIC participants’ data. Further enquiries can be directed to the corresponding author.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The ARIC Investigators are willing to share the data used in this article with a researcher for the purposes of reproducing the results, subject to completion of a data use agreement ensuring appropriate protection of the confidentiality of ARIC participants’ data. Further enquiries can be directed to the corresponding author.