Ryan T. Demmer

Periodontal Microbiota and Carotid Intima-Media Thickness The Oral Infections and Vascular Disease Epidemiology Study (INVEST)

Background—Chronic infections, including periodontal infections, may predispose to cardiovascular disease. We investigated the relationship between periodontal microbiota and subclinical atherosclerosis. Methods and Results—Of 1056 persons (age 69±9 years) with no history of stroke or myocardial infarction enrolled in the Oral Infections and Vascular Disease Epidemiology Study (INVEST), we analyzed 657 dentate subjects. Among these subjects, 4561 subgingival plaque samples were collected (average of 7 samples/subject) and quantitatively assessed for 11 known periodontal bacteria by DNA-DNA checkerboard hybridization. Extensive in-person cardiovascular risk factor measurements, a carotid scan with high-resolution B-mode ultrasound, white blood cell count, and C-reactive protein values were obtained. In 3 separate analyses, mean carotid artery intima-media thickness (IMT) was regressed on tertiles of (1) burden of all bacteria assessed, (2) burden of bacteria causative of periodontal disease (etiologic bacterial burden), and (3) the relative predominance of causative/over other bacteria in the subgingival plaque. All analyses were adjusted for age, race/ethnicity, gender, education, body mass index, smoking, diabetes, systolic blood pressure, and LDL and HDL cholesterol. Overall periodontal bacterial burden was related to carotid IMT. This relationship was specific to causative bacterial burden and the dominance of etiologic bacteria in the observed microbiological niche. Adjusted mean IMT values across tertiles of etiologic bacterial dominance were 0.84, 0.85, and 0.88 (P=0.002). Similarly, white blood cell values increased across tertiles of etiologic bacterial burden from 5.57 to 6.09 and 6.03 cells ×109/L (P=0.01). C-reactive protein values were unrelated to periodontal microbial status (P=0.82). Conclusions—Our data provide evidence of a direct relationship between periodontal microbiology and subclinical atherosclerosis. This relationship exists independent of C-reactive protein.

Relationship Between Periodontal Disease, Tooth Loss, and Carotid Artery Plaque The Oral Infections and Vascular Disease Epidemiology Study (INVEST)

BACKGROUND AND PURPOSE Chronic infections, including periodontal infections, may predispose to cardiovascular disease. The present study investigates the relationship of periodontal disease and tooth loss with subclinical atherosclerosis. METHODS We enrolled 711 subjects with a mean age of 66+/-9 years and no history of stroke or myocardial infarction in the Oral Infections and Vascular Disease Epidemiology Study. Subjects received a comprehensive periodontal examination, extensive in-person cardiovascular disease risk factor measurements, and a carotid scan using high-resolution B-mode ultrasound. Regression models were adjusted for conventional risk factors (age, sex, smoking, diabetes, systolic blood pressure, low- and high-density lipoprotein cholesterol, race-ethnicity, education, physical activity) and markers of cultural background, healthy lifestyle, and psychosocial health. RESULTS Measures of both current and cumulative periodontitis became more severe as tooth loss increased. A significant association was observed between tooth loss levels and carotid artery plaque prevalence. Among those with 0 to 9 missing teeth, 46% had carotid artery plaque, whereas among those with >or=10 missing teeth, carotid artery plaque prevalence was approximately 60% (P<0.05). CONCLUSIONS Our data suggest that tooth loss is a marker of past periodontal disease in this population and is related to subclinical atherosclerosis, thereby providing a potential pathway for a relationship with clinical events.

Gum Bug Leave My Heart Alone—Epidemiologic and Mechanistic Evidence Linking Periodontal Infections and Atherosclerosis

Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of ‘model’ periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis.

Periodontal Disease and Incident Type 2 Diabetes: Results from the First National Health and Nutrition Examination Survey and its Epidemiologic Follow-Up Study

OBJECTIVE—Type 2 diabetes and periodontal disease are known to be associated, but the temporality of this relationship has not been firmly established. We investigated whether baseline periodontal disease independently predicts incident diabetes over two decades of follow-up. RESEARCH DESIGN AND METHODS—A total of 9,296 nondiabetic male and female National Health and Nutrition Examination Survey (NHANES I) participants aged 25–74 years who completed a baseline dental examination (1971–1976) and had at least one follow-up evaluation (1982–1992) were studied. We defined six categories of baseline periodontal disease using the periodontal index. Of 7,168 dentate participants, 47% had periodontal index = 0 (periodontally healthy); the remaining were classified into periodontal index quintiles. Incident diabetes was defined by 1) death certificate (ICD-9 code 250), 2) self-report of diabetes requiring pharmacological treatment, or 3) health care facility stay with diabetes discharge code. Multivariable logistic regression models assessed incident diabetes odds across increasing levels of periodontal index in comparison with periodontally healthy participants. RESULTS—The adjusted odds ratios (ORs) for incident diabetes in periodontal index categories 1 and 2 were not elevated, whereas the ORs in periodontal index categories 3 through 5 were 2.26 (95% CI 1.56–3.27), 1.71 (1.0–2.69), and 1.50 (0.99–2.27), respectively. The OR in edentulous participants was 1.30 (1.00–1.70). Dentate participants with advanced tooth loss had an OR of 1.70 (P < 0.05) relative to those with minimal tooth loss. CONCLUSIONS—Baseline periodontal disease is an independent predictor of incident diabetes in the nationally representative sample of NHANES I.

Periodontal bacteria and hypertension: the oral infections and vascular disease epidemiology study (INVEST)

Objective Chronic infections, including periodontal infections, may predispose to cardiovascular disease. We investigated the relationship between periodontal microbiota and hypertension. Methods and results Six hundred and fifty-three dentate men and women with no history of stroke or myocardial infarction were enrolled in INVEST. We collected 4533 subgingival plaque samples (average of seven samples per participant). These were quantitatively assessed for 11 periodontal bacteria using DNA–DNA checkerboard hybridization. Cardiovascular risk factor measurements were obtained. Blood pressure and hypertension (SBP ≥140 mmHg, DBP ≥90 mmHg or taking antihypertensive medication, or self-reported history) were each regressed on the level of bacteria: considered causative of periodontal disease (etiologic bacterial burden); associated with periodontal disease (putative bacterial burden); and associated with periodontal health (health-associated bacterial burden). All analyses were adjusted for age, race/ethnicity, sex, education, BMI, smoking, diabetes, low-density lipoprotein and high-density lipoprotein cholesterol. Etiologic bacterial burden was positively associated with both blood pressure and prevalent hypertension. Comparing the highest and lowest tertiles of etiologic bacterial burden, SBP was 9 mmHg higher, DBP was 5 mmHg higher (P for linear trend was less than 0.001 in each case), and the odds ratio for prevalent hypertension was 3.05 (95% confidence interval 1.60–5.82) after multivariable adjustment. Conclusion Our data provide evidence of a direct relationship between the levels of subgingival periodontal bacteria and both SBP and DBP as well as hypertension prevalence.

Changes in Clinical and Microbiological Periodontal Profiles Relate to Progression of Carotid Intima‐Media Thickness: The Oral Infections and Vascular Disease Epidemiology Study

Background No prospective studies exist on the relationship between change in periodontal clinical and microbiological status and progression of carotid atherosclerosis. Methods and Results The Oral Infections and Vascular Disease Epidemiology Study examined 420 participants at baseline (68±8 years old) and follow‐up. Over a 3‐year median follow‐up time, clinical probing depth (PD) measurements were made at 75 766 periodontal sites, and 5008 subgingival samples were collected from dentate participants (average of 7 samples/subject per visit over 2 visits) and quantitatively assessed for 11 known periodontal bacterial species by DNA‐DNA checkerboard hybridization. Common carotid artery intima‐medial thickness (CCA‐IMT) was measured using high‐resolution ultrasound. In 2 separate analyses, change in periodontal status (follow‐up to baseline), defined as (1) longitudinal change in the extent of sites with a ≥3‐mm probing depth (Δ%PD≥3) and (2) longitudinal change in the relative predominance of bacteria causative of periodontal disease over other bacteria in the subgingival plaque (Δetiologic dominance), was regressed on longitudinal CCA‐IMT progression adjusting for age, sex, race/ethnicity, diabetes, smoking status, education, body mass index, systolic blood pressure, and low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol. Mean (SE) CCA‐IMT increased during follow‐up by 0.139±0.008 mm. Longitudinal IMT progression attenuated with improvement in clinical or microbial periodontal status. Mean CCA‐IMT progression varied inversely across quartiles of longitudinal improvement in clinical periodontal status (Δ%PD≥3) by 0.18 (0.02), 0.16 (0.01), 0.14 (0.01), and 0.07 (0.01) mm (P for trend<0.0001). Likewise, mean CCA‐IMT increased by 0.20 (0.02), 0.18 (0.02), 0.15 (0.02), and 0.12 (0.02) mm (P<0.0001) across quartiles of longitudinal improvement in periodontal microbial status (Δetiologic dominance). Conclusion Longitudinal improvement in clinical and microbial periodontal status is related to a decreased rate of carotid artery IMT progression at 3‐year average follow‐up.

Mediterranean-style diet and risk of ischemic stroke, myocardial infarction, and vascular death: the Northern Manhattan Study

BACKGROUND A dietary pattern common in regions near the Mediterranean appears to reduce risk of all-cause mortality and ischemic heart disease. Data on blacks and Hispanics in the United States are lacking, and to our knowledge only one study has examined a Mediterranean-style diet (MeDi) in relation to stroke. OBJECTIVE In this study, we examined an MeDi in relation to vascular events. DESIGN The Northern Manhattan Study is a population-based cohort to determine stroke incidence and risk factors (mean ± SD age of participants: 69 ± 10 y; 64% women; 55% Hispanic, 21% white, and 24% black). Diet was assessed at baseline by using a food-frequency questionnaire in 2568 participants. A higher score on a 0-9 scale represented increased adherence to an MeDi. The relation between the MeDi score and risk of ischemic stroke, myocardial infarction (MI), and vascular death was assessed with Cox models, with control for sociodemographic and vascular risk factors. RESULTS The MeDi-score distribution was as follows: 0-2 (14%), 3 (17%), 4 (22%), 5 (22%), and 6-9 (25%). Over a mean follow-up of 9 y, 518 vascular events accrued (171 ischemic strokes, 133 MIs, and 314 vascular deaths). The MeDi score was inversely associated with risk of the composite outcome of ischemic stroke, MI, or vascular death (P-trend = 0.04) and with vascular death specifically (P-trend = 0.02). Moderate and high MeDi scores were marginally associated with decreased risk of MI. There was no association with ischemic stroke. CONCLUSIONS Higher consumption of an MeDi was associated with decreased risk of vascular events. Results support the role of a diet rich in fruit, vegetables, whole grains, fish, and olive oil in the promotion of ideal cardiovascular health.

Epidemiologic patterns of chronic and aggressive periodontitis

The currently used definitions of chronic and aggressive periodontitis were introduced at the 1999 World Workshop for the Classification of Periodontal Diseases and Conditions (2). This revised classification system was meant to address a number of widely recognized shortcomings of the 1989 World Workshop diagnostic scheme, according to which the majority of the pathologic periodontal conditions were classified under three main categories: ‘Early Onset Periodontitis’, ‘Adult Periodontitis’, and ‘Refractory Periodontitis’. The 1999 classification did indeed address some key deficiencies of the earlier system including (i) the lack of a diagnostic category describing exclusively gingival lesions, (ii) the dependence on knowledge about the time of disease onset for distinguishing between ‘Early Onset-’ and ‘Adult’ periodontitis, and (iii) the highly heterogeneous ‘Refractory Periodontitis’ group, a term whose appropriate use required prior knowledge of the volume and quality of therapy rendered, as well as of patient compliance. Nevertheless, although one of the 1999 Classification’s explicitly expressed goals was “to discard classification terminologies that were age-dependent or required knowledge of rates of progression” (5), the new system admittedly offered only limited substantial improvement on either front. For example, one of the primary features of the newly introduced ‘Aggressive Periodontitis’ is “rapid attachment loss and bone destruction” (33). With respect to age, “circumpubertal onset” continues to constitute a key feature of Localized Aggressive Periodontitis, while Generalized Aggressive Periodontitis is suggested to “usually affect persons under 30 years of age, but patients may be older” (33). Considering that another primary diagnostic feature of Aggressive Periodontitis is “familial aggregation” of the disease, a feature that is often impossible to ascertain upon examination of a patient, one quickly recognizes that appropriate assignment of this particular diagnosis by the clinician –let alone by the epidemiologist- remains highly problematic. Nevertheless, use of the search terms ‘chronic periodontitis’ and ‘aggressive periodontitis’ in the PubMed database alone at the time of authorship of this text (July 2009) identified approximately 3,300 and 1,650 publications, respectively. Interestingly, articles using the term ‘chronic periodontitis’ covered a time span dating back to 1948, while the earliest indexed publication retrieved using ‘aggressive periodontitis’ as a keyword was published the same year, indicating that these terms have been obviously used in a variety of different contexts. Hence, given the substantial body of literature using these terms and in order to contrast with earlier reviews of the epidemiology of periodontitis that heavily relied on publications employing terminology no longer in use (9, 41), we decided to limit the present text to epidemiologic studies published over the past decade, anticipating that they would have utilized the 1999 World Workshop nomenclature. For an overview of the literature prior to 1999, the reader is referred to the above earlier quoted texts. In our review, we first address some methodological considerations related to the assessment of chronic and aggressive periodontitis in epidemiologic studies. We particularly address the issue of disease onset and the impact of age in the determination of diagnosis. Subsequently, we present current data on the global prevalence of destructive periodontitis and its variability with respect to demographic characteristics. Our review does not include the study of diagnosis-specific genetic and environmental risk factors for chronic or aggressive periodontitis, as these are dealt with in detail in Chapter 10.

Gender Differences in the Relationship Between Periodontal Disease, Tooth Loss, and Atherosclerosis

Background and Purpose— Males carry a disproportionate burden of cardiovascular disease. Because males also bear a higher burden of periodontal disease, we investigated the existence of gender differences in the postulated relationship between periodontal infections, tooth loss, and subclinical atherosclerosis. Methods— A total of 1710 randomly enrolled participants between the ages of 45 and 75 with no history of myocardial infarction or stroke received a clinical periodontal examination, carotid scan using high-resolution B-mode ultrasound, and extensive measurements for conventional cardiovascular risk factors (age, education, smoking, alcohol, body mass index, diabetes, systolic blood pressure, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol, and triglycerides) as well as markers of healthy lifestyle and social network. Results— In both genders, measures of current and long-term periodontitis worsened as tooth loss increased. In males but not females, an ≈10% difference in carotid artery plaque prevalence was observed between the lowest and highest tertiles of tooth loss (P <0.05) and long-term periodontitis (P =0.05) after multivariate adjustment. Similar patterns were observed for intima–media thickness. The influence of gender on carotid artery plaque prevalence was most evident among the younger age group (<59 years). Between genders, carotid plaque prevalence differed by 10%, 15%, and 25% across increasing levels of tooth loss, and by 5%, 15%, and 25% across increasing levels of long-term periodontitis. Conclusions— Our data suggest that tooth loss and long-term periodontitis are related to subclinical atherosclerosis in men but not women. Gender variations in cardiovascular morbidity or mortality may be explained partly by the differential contributions of novel risk factors across genders.

Periodontal Status and A1C Change: Longitudinal results from the Study of Health in Pomerania (SHIP)

OBJECTIVE Infection may be a type 2 diabetes risk factor. Periodontal disease is a chronic infection. We hypothesized that periodontal disease was related to A1C progression in diabetes-free participants. RESEARCH DESIGN AND METHODS The Study of Health in Pomerania (SHIP) is a population-based cohort in Germany including 2,973 diabetes-free participants (53% women; aged 20–81 years). Participants were categorized into four groups according to increasing baseline periodontal disease levels (percentage of sites per mouth with attachment loss ≥5 mm, determined a priori); sample sizes for each respective category were 1,122, 488, 463, and 479 (241 participants were edentulous). Mean absolute changes (year 5 minus baseline) in A1C (ΔA1C) were regressed across periodontal categories while adjusting for confounders (e.g., age, sex, smoking, obesity, physical activity, and family history). RESULTS Across baseline periodontal disease categories, ΔA1C ± SEM values were 0.023 ± 0.02, 0.023 ± 0.02, 0.065 ± 0.03, and 0.106 ± 0.03 (Ptrend = 0.02), yielding an approximate fivefold increase in the absolute difference in ΔA1C when dentate participants in the highest versus lowest periodontal disease category were compared; these results were markedly stronger among participants with high-sensitivity C-reactive protein ≥1.0 mg/l (Pinteraction = 0.01). When individuals who had neither baseline periodontal disease nor deterioration in periodontal status at 5 years were compared with individuals with both poor baseline periodontal health and longitudinal periodontal deterioration, mean ΔA1C values were 0.005 vs. 0.143% (P = 0.003). CONCLUSIONS Periodontal disease was associated with 5-year A1C progression, which was similar to that observed for a 2-SD increase in either waist-to-hip ratio or age in this population.