Abstract
Background:
Periodontal disease (PD) has been linked to a range of cardiometabolic disorders. However, the association between PD and composite cardiovascular risk has not been studied. We hypothesized that PD would be associated with an elevated atherosclerotic cardiovascular risk (ASCVD) score.
Methods:
This analysis included 12,402 participants (age 42.7 ± 18.6 years, 46.8% male, 69.6% Caucasian) from the Third National Health and Nutrition Examination Survey. Participants with a history of myocardial infarction or stroke were excluded. PD was defined as moderate (≥4mm attachment loss or ≥5 mm pocket depth in ≥2 mesial sites) or severe (≥6 mm attachment loss in ≥2 mesial sites and ≥5 mm pocket depth in ≥1 mesial site). ASCVD scores were classified categorically: low (<5.0%), borderline (5.0–7.4%), intermediate (7.5–19.9%), and high (≥20.0%). Linear and multinomial logistic regression were used to examine the association between PD and ASCVD score.
Results:
Approximately 12.1% (n = 1499) of participants had PD. Moderate periodontitis was associated with a greater than five-fold increased odds of high-risk ASCVD score [OR (95% CI): 5.40 (4.63–6.31), p-value <0.001]. Severe periodontitis was associated with a greater than seven-fold increased odds of high-risk ASCVD score [OR (95% CI): 7.15 (5.14–9.96), p-value <0.001]. Composite periodontitis (moderate or severe) was associated with a 7.0% increase in ASCVD score [β (95% CI): 7.01 (6.53–7.50)] when modeled linearly.
Conclusions:
PD is associated with elevated ASCVD score. Patients with PD should be counseled regarding their elevated cardiovascular risk and risk reduction strategies should be implemented with an emphasis on routine dental care.
Keywords: periodontal disease, Cardiovascular risk factors, Periodontitis, Atherosclerosis
INTRODUCTION
Periodontal disease (PD) is characterized by chronic inflammation of the gingiva extending into the adjacent attachment apparatus leading to destruction of the periodontal ligaments and loss of supporting bone. This is characterized clinically by gingival inflammation and bleeding, periodontal pocket formation, attachment loss, gingival recession, and tooth mobility.1 The burden of PD is significant; its moderate form affects 42% of adults while its severe form affects 7.8% of adults.2
Atherosclerosis is an inflammatory, multifactorial illness in which lipids build up inside the arteries leading to hardening and narrowing over time. As a consequence, there is a decreased flow of blood and consequent impaired oxygen delivery causing serious problems including myocardial infarction, stroke, and premature death.3 Currently, there are several proposed mechanisms by which PD may trigger parallel pathways leading to atherosclerosis through direct and indirect effect of oral bacteria as well as raised concentration of inflammatory biomarkers.4
The Atherosclerotic Cardiovascular Disease (ASCVD) risk score is a validated composite risk assessment for estimating ten-year risk for major cardiovascular events.5 Given the observed association between PD and atherosclerosis, we hypothesized that PD would be associated with elevated composite cardiovascular risk as manifested by the ASCVD risk score.
METHODS
The Third National Health and Nutrition Examination Survey (NHANES-III) is a survey of the population of the United States. NHANES-III data were collected from 1988–1994 through both interviews and laboratory examinations.6
In the examined cohort, we excluded participants <18 years of age as well as those with a history of myocardial infarction or stroke. Age, gender, race, and smoking status were defined by self-report. Participants without periodontal data were excluded from the analysis.
Periodontal assessments were performed on randomly assigned half-mouths - one upper quadrant and one lower quadrant.6 The buccal and mesial surfaces of each tooth were assessed for the following: gingival bleeding, calculus burden, gingival recession, and pocket depth. Attachment loss was composed of two variables: 1) the distance from the free gingival margin to the cemento-enamel junction, and 2) the distance from the free gingival margin to the bottom of the sulcus (pocket depth). Attachment loss was calculated as the difference between these two variables.6 PD was defined based on Centers for Disease Control and Prevention criteria for population-based studies.7 Moderate PD was defined as at least 2 mesial sites with ≥4 mm attachment loss or at least 2 mesial sites with ≥5 mm pocket depth. Severe PD was defined as at least 2 mesial sites with ≥6mm attachment loss and at least 1 mesial site with ≥5mm pocket depth. A composite definition of PD was defined as participants with moderate or severe PD.
Composite cardiovascular risk was assessed using the American College of Cardiology/American Heart Association 10-year Atherosclerotic Cardiovascular Risk (ASCVD) Score.5 The ASCVD score is a validated risk assessment tool that estimates cardiovascular risk using a pooled cohort equation that uses age, race, gender, cholesterol, blood pressure, and comorbidities to provide a 10-year estimate of risk for major cardiovascular events.5 ASCVD scores were reported as percentages and modeled both linearly and categorically. When modeled categorically, the following risk intervals were used: low (<5.0%), borderline (5.0–7.4%), intermediate (7.5–19.9%), and high (≥20.0%).
Diabetes was defined as hemoglobin A1c ≥6.5%, fasting serum glucose ≥126 mg/dL or use of an antihyperglycemic. Hypertension was defined as systolic blood pressure ≥130 mmHg or diastolic blood pressure ≥80 mmHg or use of an antihypertensive per American Heart Association/American College of Cardiology guidelines.8 We defined obesity as body mass index ≥30 kg/m2.
Population characteristics were compared based on presence of periodontal disease. Continuous variables were reported as mean ± standard deviation. Categorical variables were reported as percentage and frequency. A chi-square test was used to compare categorical variables and a student’s t-test was used to compare continuous variables.
Linear regression was used to estimate the association between PD and ASCVD score when ASCVD score was modeled as a continuous variable. Results were reported as β coefficients with corresponding 95% Confidence Interval (95% CI). Multinomial logistic regression was used to estimate the association between PD and ASCVD score when ASCVD score was modeled categorically; the low risk ASCVD score category was used as the reference level. Results were reported as odds ratios (OR) with corresponding 95% CI. Since age, diabetes, gender, ethnicity, smoking status, and hyperlipidemia are all factors used to calculate the ASCVD score, these variables were not adjusted for in the regression models. Associations were also measured in subgroups stratified by race, gender, hypertension, obesity, diabetes, hyperlipidemia, and smoking status.
All statistical analyses were conducted using RStudio version 1.3.1093 (Boston, MA) and p-values were considered significant if <0.05.
Ethical Approval and Informed Consent
Ethical approval was not required as the data used were from the Third National Health and Nutrition Examination Survey (NHANES-III). All participants provided written consent at the time of study enrollment. Data from NHANES-III are public access, so no additional permissions were required.
RESULTS
After exclusions, 12,402 participants (age 42.7 ± 18.6 years, 46.8% male, 69.6% Whites) were included in the analysis. Approximately 12.1% (n = 1499) of participants had moderate or severe PD. Population characteristics stratified by PD status are shown in Table 1. Participants with PD were more likely to be older, male, and be of non-white race. They were also more likely to have hypertension, diabetes, obesity, and be current smokers. Participants with PD also exhibited higher levels of total cholesterol; high-density lipoprotein was significantly reduced in those with severe PD when compared to those without PD. Participants with PD also had higher mean ASCVD risk scores.
TABLE 1.
Population characteristicsb.
| Characteristics | Periodontal Disease (Mean ± SD or n (%)) |
||
|---|---|---|---|
| None | Moderate | Severe | |
| Participants | 10,903 (87.9%) | 1,240 (10.0%) | 259 (2.1%) |
| Age (years) | 40.9 ± 18.2 | 56.0 ± 16.6a | 55.7 ± 13.9a |
| Men | 4897 (44.9%) | 732 (59.0%)a | 178 (68.7%)a |
| Race | |||
| White | 7673 (70.4%) | 815 (65.7%)a | 142 (54.8%)a |
| Non-white | 3230 (29.6%) | 425 (34.2%)a | 117 (45.2%)a |
| Hypertension | 4406 (40.4%) | 759 (61.2%)a | 178 (68.7%)a |
| Obesity | 2613 (24.0%) | 339 (27.3%)a | 81 (31.3%)a |
| Diabetes | 751 (6.9%) | 216 (17.4%)a | 62 (23.9%)a |
| Total Cholesterol (mg/dL) | 199 ± 43.3 | 212 ± 44.5a | 216 ± 40.9a |
| HDL (mg/dL) | 51.5 ± 15.1 | 50.6 ± 17.4 | 49.5 ± 15.0a |
| Current smoker | 2648 (24.3%) | 453 (36.5%)a | 116 (44.8%)a |
| ASCVD Risk Score (%) | 6.1 ± 8.8 | 12.9 ± 10.7a | 14.0 ± 10.2a |
P-value <0.05 compared with no periodontal disease.
Abbreviations: HDL = high-density lipoprotein; ASCVD = atherosclerotic cardiovascular disease.
When modeled linearly, composite PD (moderate or severe) was associated with a 7.0% relative increase in ASCVD score [β (95% CI): 7.01 (6.53–7.50)]. This result is shown in Fig. 1.
FIG. 1.
Association of composite periodontal disease and atherosclerotic cardiovascular disease (ASCVD) risk score. Scatter plot of each participant and the corresponding ASCVD risk score. Composite periodontal disease includes moderate or severe disease. The fitted linear regression line with the corresponding standard error is shown.
Table 2 shows the results of the multinomial logistic regression when modeled categorically. Moderate PD was associated with increased odds of borderline [OR (95% CI): 3.72 (2.98–4.63), p < 0.001], intermediate [OR (95% CI): 4.96 (4.26–5.78), p < 0.001], and high [OR (95% CI): 5.40 (4.63–6.31), p < 0.001] ASCVD score when low ASCVD score was used as the reference level. Severe PD was associated with increased odds of borderline [OR (95% CI): 4.28 (2.65–6.90), p < 0.001], intermediate [OR (95% CI): 7.51 (5.46–10.32), p < 0.001], and high [OR (95% CI): 7.15 (5.14–9.96), p < 0.001] ASCVD score when low ASCVD score was used as the reference level. Composite PD (moderate or severe) was associated with increased odds of borderline [OR (95% CI): 3.80 (3.09–4.66), p < 0.001], intermediate [OR (95% CI): 5.33 (4.63–6.13), p < 0.001], and high [OR (95% CI): 5.66 (4.90–6.53), p < 0.001] ASCVD score when low ASCVD score was used as the reference level.
TABLE 2.
Association of periodontal disease and ASCVD risk category.
| Periodontal Disease | Reference Level | ASCVD Risk Category |
||
|---|---|---|---|---|
| Borderlineb OR (95% CI) | Intermediatec OR (95% CI) | Highd OR (95% CI) | ||
| Moderate | No Disease | 3.72 (2.98–4.63)a | 4.96 (4.26–5.78)a | 5.40 (4.63–6.31)a |
| Severe | No Disease | 4.28 (2.65–6.90)a | 7.51 (5.46–10.32)a | 7.15 (5.14–9.96)a |
| Moderate or Severe | No Disease | 3.80 (3.09–4.66)a | 5.33 (4.63–6.13)a | 5.66 (4.90–6.53)a |
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; OR (95% CI) = Odds Ratio (95% Confidence Interval).
P-value <0.001.
Borderline = ASCVD score 5.0–7.4%.
Intermediate = ASCVD score 7.5%-19.9%.
High = ASCVD score ≥20%.
Table 3 summarizes the results of the multinomial regression when stratified by sub-groups.
TABLE 3.
Association of periodontal disease and ASCVD risk category among sub-groups.
| Sub-group | ASCVD Risk Categorya |
|||
|---|---|---|---|---|
| Borderlineb OR (95% CI) | Intermediatec OR (95% CI) | Highd OR (95% CI) | ||
| Race | Non-white | 4.15 (3.00–5.74) | 5.25 (4.14–6.65) | 5.51 (4.23–7.18) |
| White | 3.71 (2.84–4.84) | 5.72 (4.78–6.84) | 6.33 (5.30–7.55) | |
| Gender | Men | 3.95 (3.00–5.18) | 6.28 (5.21–7.58) | 6.08 (5.00–7.38) |
| Women | 3.40 (2.48–4.64) | 3.66 (2.92–4.59) | 4.72 (3.79–5.88) | |
| Hypertension | Present | 2.73 (2.06–3.63) | 3.78 (3.10–4.62) | 4.20 (3.47–5.09) |
| Absent | 4.46 (3.30–6.04) | 6.44 (5.17–8.03) | 5.54 (3.99–7.69) | |
| Obesity | Present | 2.06 (1.40–3.06) | 3.48 (2.70–4.48) | 3.60 (2.71–4.78) |
| Absent | 4.78 (3.76–6.08) | 6.25 (5.27–7.40) | 6.64 (5.61–7.85) | |
| Diabetes | Present | 1.76 (0.89–3.49) | 1.85 (1.18–2.92) | 2.02 (1.33–3.09) |
| Absent | 3.81 (3.08–4.73) | 5.42 (4.66–6.30) | 5.43 (4.60–6.41) | |
| Hyperlipidemia | Present | 2.87 (2.23–3.69) | 4.22 (3.55–5.02) | 4.42 (3.70–5.27) |
| Absent | 5.54 (3.86–7.95) | 7.04 (5.39–9.19) | 7.90 (6.00–10.4) | |
| Tobacco Smoking Status | Smoker | 2.74 (2.04–3.68) | 4.00 (3.18–5.03) | 4.83 (3.70–6.32) |
| Nonsmoker | 3.88 (2.90–5.18) | 5.80 (4.85–6.94) | 6.33 (5.33–7.53) | |
Abbreviations: ASCVD = atherosclerotic cardiovascular disease; OR (95% CI) = Odds Ratio (95% Confidence Interval).
Association of moderate or severe periodontal disease and ASCVD risk category.
Borderline = ASCVD score 5.0–7.4%.
Intermediate = ASCVD score 7.5%–19.9%.
High = ASCVD score ≥20%.
DISCUSSION
PD is strongly associated with elevated risk for major cardiovascular events as evidenced by an elevated ASCVD risk score. This was observed when the ASCVD risk score was modeled as both a linear and categorical variable among participants without any known history of cardiovascular disease. This association persisted in all subgroup stratifications analyzed. Together, these findings suggest that PD may be an emerging modifiable risk factor for atherosclerotic cardiovascular disease.
PD is a multifactorial inflammatory disease. It is thought to originate from host- bacterial interaction attributable to multiple infectious agents, interconnected cellular and humoral host immune responses, and local as well as systemic predisposing factors. It is clinically characterized by the formation of tooth plaque through multiplexes and various microbial biofilms. Products liberated from this biofilm, including endotoxins and antigenic substances, cause increases in the immunological response. Regional microbiota imbalance causes localized inflammatory reactions and host immune system over-activation directly promotes osteoclastic activity causing alveolar bone resorption.9
Microorganisms that cause periodontitis were recently shown to function as reservoirs for infections which induce systemic inflammatory responses. Gram negative microorganisms that are found in the bacterial biofilm cause both dental and systemic disorders through 2 parallel pathways: (1) leukotoxins and endotoxins released from Aggregatibacter actinomycetemcomitans directly affect the periodontium via cytokine release. The resultant inflammation damages the periodontium and leads to resorption of the surrounding alveolar bone. (2) Porphyromonas gingivalis produces both proteinases and endotoxins that directly invade internal organs resulting in elevated secretion of cytokines with similar inflammatory consequences.10
Regarding the connection to atherosclerosis, the presence of oral bacteria, mainly gram-negative bacteria, can adhere, invade, and proliferate in endothelial cells and induce platelets aggregation which leads to thrombus formation. Exaggerated host esponse to the microbial products and lipopolysaccharides reflected in the release of high levels of pro-inflammatory mediators such as C-reactive protein, interleukin-18 and heat shock protein which are considered critical biomarkers and risk factors for developing atherosclerosis. Finally, lipopolysaccharides released from bacterial accumulation are transferred to the serum as a result of bacteremia that may have a direct effect on the endothelial cells thus promoting atherosclerosis.11
People with PD are more likely to develop heart disease than healthy persons. This is currently thought to be due to increased atherosclerotic burden.12 This is likely one of the primary drivers for the observed increase in ASCVD risk score in our analysis. In addition, hypertension is also known to aggravate atherosclerosis due to its physical stress on the arterial walls. The chronic inflammatory processes of PD result in an imbalance of free radicals and antioxidants as well as endothelial malfunction which have been shown to be associated with hypertension13; this is also a likely contributor to the observed elevation in ASCVD risk score among this population.
Another major cardiovascular risk factor is diabetes; PD risk in diabetes is triple compared to those without diabetes. Further, data have shown that the risk of cardiovascular death is three times greater in diabetic patients with severe PD versus diabetic patients without PD14. The mechanism behind these findings is thought to be similar and related to chronic gram-negative infections and endotoxemia inducing insulin resistance and worsening of metabolic control in diabetic patients. Interestingly, there is evidence that following periodontal therapy (e.g., non-surgical periodontal treatment such as scaling and root planing), a marked improvement in glycemic control among diabetic patients was achieved.15
Considering smoking, smokers are more likely to be infected with Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis, which are the primary bacterial agents associated with PD. In addition, smoking causes a diminished response to periodontal treatment due to decrease in serum lymphocytes and impaired immune response.16 Nicotine present in cigarettes plays a critical role in decreasing blood flow throughout body and subsequently decreases gingival blood flow leading to impaired revascularization in hard and soft tissues.17 Finally, the toxic combustion products in cigarettes are thought to directly contribute to atherosclerosis, yet another exacerbating factor among those with pre-existent PD.18
Periodontal treatment is an essential step to decrease bacterial overload and to prevent the progression of dental and systemic malfunctions. Conservative or non-surgical therapy includes supragingival and subgingival scaling, root planing, and adjunctive use of chemical agents such as antimicrobial mouthwashes, local antibiotic therapy and anti-inflammatory drugs. Surgical therapy includes procedures that involve gingivectomy, apically displaced flaps, and flaps with bone graft or with barrier membranes, ridge augmentation, root coverage, and crown lengthening.19
The most important part of periodontal treatment is prevention. Basic prophylactic dental measures include routine dental care at home and regular dental visits to monitor dental health. These measures have proven to decrease the likelihood of development of atherosclerosis as periodontal treatment decreases the biofilm load thereby lowering the level of inflammatory products that play an important role in its development.20
This study suffers from many limitations. The cross-sectional nature of the cohort is subject to recall and detection bias. Further, we do not have information regarding incidence of atherosclerotic cardiovascular events over time. The calculated ASCVD scores are based on metrics collected at the time of interview and therefore do not necessarily capture longitudinal risk. Cross-sectional studies are useful for generating hypotheses only, therefore the association between periodontal disease and ASCVD risk should be further scrutinized in a prospective, longitudinal cohort to further validate these findings and determine a possible causal relationship. In addition, since periodontal assessments were only performed on randomly assigned half-mouths, true disease prevalence may have been underestimated.
Strengths of this analysis include an ethnically diverse study population and novel use of the ASCVD score as a measure of composite cardiovascular risk.
CONCLUSIONS
PD is associated with elevated cardiovascular risk as evidenced by a positive association with ASCVD score. These findings provide evidence that PD may be an emerging modifiable risk factor for atherosclerotic cardiovascular disease. Patients with PD should be counseled regarding their elevated risk for major cardiovascular events and appropriate risk reduction strategies should be implemented with an emphasis on routine dental care and optimization of modifiable risk factors.
ACKNOWLEDGEMENTS
There were no further contributions to this project beyond those of the listed authors.
Footnotes
CONFLICTS OF INTEREST STATEMENT
The authors whose names are listed certify that they have no affiliations with or involvement in any organization or entity with any financial interest or non-financial interest in the subject matter or materials discussed in this manuscript.
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