Systemic Metabolic Signatures of Oral Diseases.

Systemic metabolic signatures of oral diseases have been rarely investigated, and prospective studies do not exist. We analyzed whether signs of current or past infectious/inflammatory oral diseases are associated with circulating metabolites. Two study populations were included: the population-based Health-2000 (n = 6,229) and Parogene (n = 452), a cohort of patients with an indication to coronary angiography. Health-2000 participants (n = 4,116) provided follow-up serum samples 11 y after the baseline. Serum concentrations of 157 metabolites were determined with a nuclear magnetic resonance spectroscopy-based method. The associations between oral parameters and metabolite concentrations were analyzed using linear regression models adjusted for age, sex, number of teeth, smoking, presence of diabetes, and education (in Health-2000 only). The number of decayed teeth presented positive associations with low-density lipoprotein diameter and the concentrations of pyruvate and citrate. Negative associations were found between caries and the unsaturation degree of fatty acids (FA) and relative proportions of docosahexaenoic and omega-3 FAs. The number of root canal fillings was positively associated with very low-density lipoprotein parameters, such as diameter, cholesterol, triglycerides, and number of particles. Deepened periodontal pockets were positively associated with concentrations of cholesterol, triglycerides, pyruvate, leucine, valine, phenylalanine, and glycoprotein acetyls and negatively associated with high-density lipoprotein (HDL) diameter, FA unsaturation degree, and relative proportions of omega-6 and polyunsaturated FAs. Bleeding on probing (BOP) was associated with increased concentrations of triglycerides and glycoprotein acetyls, as well as decreased proportions of omega-3 and omega-6 FAs. Caries at baseline predicted alterations in apolipoprotein B-containing lipoproteins and HDL-related metabolites in the follow-up, and both caries and BOP were associated with changes in HDL-related metabolites and omega-3 FAs in the follow-up. Signs of current or past infectious/inflammatory oral diseases, especially periodontitis, were associated with metabolic profiles typical for inflammation. Oral diseases may represent a modifiable risk factor for systemic chronic inflammation and thus cardiometabolic disorders.

Carotid artery calcification in panoramic radiographs associates with oral infections and mortality.

AIM: To study the prevalence of carotid artery calcification (CAC) in relation to apical and marginal periodontitis, subgingival dysbiotic bacterial species and serum and saliva immune responses against them. In addition, the aim was to analyse the association of CAC with angiographically verified coronary artery disease (CAD) and mortality. METHODOLOGY: In the present random Parogene cohort, the patients had an indication for coronary angiography. Apical and marginal periodontitis were diagnosed during clinical and radiographic oral examinations, and CAC on panoramic radiographs (n = 492). Presence and severity of CAD were registered from angiography. Subgingival dysbiotic bacterial species were quantitated using checkerboard DNA-DNA-hybridization, and serum and saliva antibody levels were determined by immunoassays. The cohort was followed-up for 10 years or until death (median 9.9, range 0.21-10.4) via linkage to the national death register. The statistical models were adjusted for age, gender, smoking, hypertension, diabetes and dyslipidemia. RESULTS: A total of 102 (20.7%) patients had detectable CAC, which was moderate in 81 (16.4%) and severe in 21 (4.3%). CAC was associated (OR, 95% CI) with severe apical periodontitis (2.25, 1.15-4.41), root canal fillings (1.15, 1.04-1.26), alveolar bone loss (2.66, 1.21-5.84), severe periodontal inflammation (2.23, 1.11-4.47), high level of gram-negative subgingival species (2.73, 1.34-5.50), saliva IgG against dysbiotic species (1.05, 1.01-1.10/unit) and severe (2.58, 1.36-4.90) and chronic (2.13, 1.15-3.93) CAD. A total of 105 (20.7%) patients died during the follow-up and 53 (10.4%) deaths were because of cardiovascular diseases (CVD). Severe CAC predicted worse survival with HRs (95% CI) of 3.08 (1.58-6.06) for all-cause and 3.43 (1.42-8.25) for CVD death. CONCLUSIONS: CAC on panoramic tomography was associated with (i) apical and marginal periodontitis and dysbiotic bacterial species giving rise to an immunological response, and with (ii) severe, chronic CAD and increased mortality. The results further emphasize the role of oral infections in CAD and the importance of referring a patient with CAC for a cardiovascular evaluation.

Association between dental factors and mortality.

AIM: To study whether oral parameters such as endodontic infections, root canal fillings, number of teeth or wearing removable dentures at baseline are associated with cardiovascular- and all-cause mortality in a follow-up of approximately 8 years. METHODOLOGY: The Finnish Parogene cohort consists of 508 Finnish adults (mean age 63.3 years, SD 9.1) with cardiac symptoms, all of whom had undergone coronary angiography for accurate baseline coronary status. Extensive clinical and radiographic oral examinations were performed, and additional data were acquired from medical records and questionnaires. Root canal fillings and endodontic lesions, as well as their co-occurrence, were determined from panoramic radiographs. The mortality data were assessed via record linkage with the Finnish Causes of Death register (mean follow-up time 7.81 years, SD 1.45 years). A total of n = 471 dentate patients were included in the statistical analyses. RESULTS: A total of n = 69 deaths were recorded, of which n = 41 were due to cardiovascular diseases (CVDs, ICD-10 I00-I99). The deceased had fewer root canal fillings (mean 1.57; SD 1.64 vs. mean 2.30; SD 2.34, P = 0.03) than the survivors. The number of missing teeth was associated with smoking, occluded coronary arteries and diabetes. Cox regression with Firth's penalized maximum-likelihood method using age as timescale revealed an inverse association (HR; 95%CI) between mortality and number of teeth (all-cause 0.91; 0.86-0.96, CVD mortality 0.89; 0.83-0.96), use of removable dentures (all-cause 0.24; 0.09-0.62, CVD mortality 0.20; 0.06-0.72), root canal fillings (all-cause 0.82; 0.70-0.94, CVD mortality 0.79; 0.63-0.96) and having root canal fillings in all teeth with apical rarefactions (all-cause 0.27; 0.06-0.79, CVD mortality 0.09; 0.01-0.63), when gender, smoking, occluded coronary arteries, periodontal inflammatory burden index and the number of teeth were adjusted for. CONCLUSIONS: The number of missing teeth appeared to be the strongest predictor of mortality in this study, whereas endodontic infections per se had no independent association. Nevertheless, signs of professional intervention in these problems, such as root canal fillings and removable dentures, appeared to be associated with improved survival, which might partly be explained by the utilization of healthcare services.

Associations among Periodontitis, Calcified Carotid Artery Atheromas, and Risk of Myocardial Infarction.

Cardiovascular disease is a common cause of morbidity and premature mortality. Cardiovascular disease can be prevented when risk factors are identified early. Calcified carotid artery atheromas (CCAAs), detected in panoramic radiographs, and periodontitis have both been associated with increased risk of cardiovascular disease. This case-control study aimed to 1) investigate associations between periodontitis and CCAA detected in panoramic radiographs and 2) determine the risk of future myocardial infarctions due to CCAA combined with periodontitis. We evaluated 1,482 participants (738 cases and 744 controls) with periodontitis and CCAAs recruited from the PAROKRANK study (Periodontitis and Its Relation to Coronary Artery Disease). Participants were examined with panoramic radiographs, including the carotid regions. Associations between myocardial infarction and periodontitis combined with CCAA were evaluated in 696 cases and 696 age-, sex-, and residential area-matched controls. Periodontitis was evaluated radiographically (as degree of bone loss) and with a clinical periodontal disease index score (from clinical and radiographic assessments). We found associations between CCAA and clinical periodontal disease index score among cases (odds ratio [OR], 1.51; 95% CI, 1.09 to 2.10; P = 0.02) and controls (OR, 1.70; 95% CI, 1.22 to 2.38; P < 0.01), although not between CCAA and the degree of bone loss. In a multivariable model, myocardial infarction was associated with CCAA combined with periodontitis, as assessed by degree of bone loss (OR, 1.75; 95% CI, 1.11 to 2.74; P = 0.01). When the cohort was stratified by sex, only men showed a significant association between myocardial infarction and CCAA combined with periodontitis. Participants with clinically diagnosed periodontitis exhibited CCAA in panoramic radiographs more often than those without periodontitis, irrespective of the presence of a recent myocardial infarction. Participants with combined periodontitis and CCAA had a higher risk of having had myocardial infarction as compared with participants with either condition alone. These findings implied that patients in dental care might benefit from dentists assessing panoramic radiographs for CCAA-particularly, patients with periodontitis who have not received any preventive measures for cardiovascular disease.

Salivary IgA to MAA-LDL and Oral Pathogens Are Linked to Coronary Disease.

A large body of literature has established the link between periodontal disease and cardiovascular disease. Oxidized low-density lipoproteins (OxLDLs) have a crucial role in atherosclerosis progression through initiation of immunological response. Monoclonal IgM antibodies to malondialdehyde-modified low-density lipoprotein (MDA-LDL) and to malondialdehyde acetaldehyde-modified low-density lipoprotein (MAA-LDL) have been shown to cross-react with the key virulence factors of periodontal pathogens Porphyromonas gingivalis and Aggregatibacter actinomycetemcomitans. We have previously shown that salivary IgA antibodies to MAA-LDL cross-react with P. gingivalis in healthy humans. In this study, we aim to assess whether oral mucosal immune response represented by salivary IgA to MAA-LDL and oral pathogens is associated with coronary artery disease (CAD). Also, the molecular mimicry through antibody cross-reaction between salivary IgA to MAA-LDL and oral pathogens was evaluated. The study subjects consisted of 451 patients who underwent a coronary angiography with no CAD ( n = 133), stable CAD ( n = 169), and acute coronary syndrome (ACS, n = 149). Elevated salivary IgA antibody levels to MAA-LDL, Rgp44 (gingipain A hemagglutinin domain of P. gingivalis), and Aa-HSP60 (heat shock protein 60 of A. actinomycetemcomitans) were discovered in stable-CAD and ACS patients when compared to no-CAD patients. In a multinomial regression model adjusted for known cardiovascular risk factors, stable CAD and ACS were associated with IgA to MAA-LDL ( P = 0.016, P = 0.043), Rgp44 ( P = 0.012, P = 0.004), Aa-HSP60 ( P = 0.032, P = 0.030), Tannerella forsythia ( P = 0.002, P = 0.004), Porphyromonas endodontalis ( P = 0.016, P = 0.020), Prevotella intermedia ( P = 0.038, P = 0.005), and with total IgA antibody concentration ( P = 0.002, P = 0.016). Salivary IgA to MAA-LDL showed cross-reactivity with the oral pathogens tested in the study patients. The study highlights an association between salivary IgA to MAA-LDL and atherosclerosis. However, whether salivary IgA to MAA-LDL and the related oral humoral responses play a causal role in the development in the CAD should be elucidated in the future.

Biofilm formation - what we can learn from recent developments.

Although biofilms have been observed early in the history of microbial research, their impact has only recently been fully recognized. Biofilm infections, which contribute to up to 80% of human microbial infections, are associated with common human disorders, such as diabetes mellitus and poor dental hygiene, but also with medical implants. The associated chronic infections such as wound infections, dental caries and periodontitis significantly enhance morbidity, affect quality of life and can aid development of follow-up diseases such as cancer. Biofilm infections remain challenging to treat and antibiotic monotherapy is often insufficient, although some rediscovered traditional compounds have shown surprising efficiency. Innovative anti-biofilm strategies include application of anti-biofilm small molecules, intrinsic or external stimulation of production of reactive molecules, utilization of materials with antimicrobial properties and dispersion of biofilms by digestion of the extracellular matrix, also in combination with physical biofilm breakdown. Although basic principles of biofilm formation have been deciphered, the molecular understanding of the formation and structural organization of various types of biofilms has just begun to emerge. Basic studies of biofilm physiology have also resulted in an unexpected discovery of cyclic dinucleotide second messengers that are involved in interkingdom crosstalk via specific mammalian receptors. These findings even open up new venues for exploring novel anti-biofilm strategies.

Statins in nonsurgical and surgical periodontal therapy. A systematic review and meta-analysis of preclinical in vivo trials.

The cholesterol-lowering drugs, statins, possess anti-inflammatory, antimicrobial and pro-osteogenic properties, and thus have been tested as an adjunct to periodontal treatment. The present systematic review aimed to answer the following focused research question: What is the effect of local and/or systemic statin use on periodontal tissues in preclinical in vivo studies of experimentally induced periodontitis (EIP) and/or acute/chronified periodontal defect (ACP) models? A literature search (of Medline/PubMed, Embase/Ovid, CENTRAL/Ovid) using the following main eligibility criteria was performed: (i) English or German language; (ii) controlled preclinical in vivo trials; (iii) local and/or systemic statin use in EIP and/or ACP models; and (iv) quantitative evaluation of periodontal tissues (i.e., alveolar bone level/amount, attachment level, cementum formation, periodontal ligament formation). Sixteen studies in EIP models and 7 studies in ACP models evaluated simvastatin, atorvastatin or rosuvastatin. Thirteen of the EIP (81%) and 2 of the ACP (29%) studies presented significantly better results in terms of alveolar bone level/amount in favor of statins. Meta-analysis based on 14 EIP trials confirmed a significant benefit of local and systemic statin use (P < .001) in terms of alveolar bone level/amount; meta-regression revealed that statin type exhibited a significant effect (P = .014) in favor of atorvastatin. Three studies reported a significantly higher periodontal attachment level in favor of statin use (P < .001). Complete periodontal regeneration was never observed; furthermore, statins did not exert any apparent effect on cementum formation. Neither local nor systemic use of statins resulted in severe adverse effects. Statin use in periodontal indications has a positive effect on periodontal tissue parameters, supporting the positive results already observed in clinical trials. Nevertheless, not all statins available have been tested so far, and further research is needed to identify the maximum effective concentration/dose and optimal carrier.

Association of Endodontic Lesions with Coronary Artery Disease.

An endodontic lesion (EL) is a common manifestation of endodontic infection where Porphyromonas endodontalis is frequently encountered. EL may associate with increased risk for coronary artery disease (CAD) via similar pathways as marginal periodontitis. The aim of this cross-sectional study was to delineate the associations between EL and CAD. Subgingival P. endodontalis, its immune response, and serum lipopolysaccharide were examined as potential mediators between these 2 diseases. The Finnish Parogene study consists of 508 patients (mean age, 62 y) who underwent coronary angiography and extensive clinical and radiographic oral examination. The cardiovascular outcomes included no significant CAD ( n = 123), stable CAD ( n = 184), and acute coronary syndrome (ACS; n = 169). EL was determined from a panoramic tomography. We combined data of widened periapical spaces (WPSs) and apical rarefactions to a score of EL: 1, no EL ( n = 210); 2, ≥1 WPS per 1 apical rarefaction ( n = 222); 3, ≥2 apical rarefactions ( n = 76). Subgingival P. endodontalis was defined by checkerboard DNA-DNA hybridization analysis, and corresponding serum antibodies were determined by ELISA. In our population, 50.4% had WPSs, and 22.8% apical rarefactions. A total of 51.2% of all teeth with apical rarefactions had received endodontic procedures. Subgingival P. endodontalis levels and serum immunoglobulin G were associated with a higher EL score. In the multiadjusted model (age, sex, smoking, diabetes, body mass index, alveolar bone loss, and number of teeth), having WPSs associated with stable CAD (odds ratio [OR] = 1.94, 95% confidence interval [95% CI] = 1.13 to 3.32, P = 0.016) and highest EL score were associated with ACS (OR = 2.46, 95% CI = 1.09 to 5.54, P = 0.030). This association was especially notable in subjects with untreated teeth with apical rarefactions ( n = 59, OR = 2.72, 95% CI = 1.16 to 6.40, P = 0.022). Our findings support the hypothesis that ELs are independently associated with CAD and in particular with ACS. This is of high interest from a public health perspective, considering the high prevalence of ELs and CAD.

Antimicrobial activity of polyhexamethylene guanidine phosphate in comparison to chlorhexidine using the quantitative suspension method.

BACKGROUND: Polyhexamethylene guanidine phosphate (PHMG-P) belongs to the polymeric guanidine family of biocides and contains a phosphate group, which may confer better solubility, a detoxifying effect and may change the kinetics and dynamics of PHMG-P interactions with microorganisms. Limited data regarding PHMG-P activity against periodontopathogenic and cariogenic microorganisms necessitates studies in this area. Aim is to evaluate polyhexamethylene guanidine phosphate antimicrobial activity in comparison to chlorhexidine. METHODS: Quantitative suspension method was used enrolling Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli and Candida albicans, Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Streptococcus mutans and Lactobacillus acidophilus. RESULTS: Both tested antiseptics at their clinically-used concentrations, of 0.2% (w/v) and 1% (w/v), correspondingly provided swift bactericidal effects against S. aureus, P. aeruginosa, E. coli and C. albicans, A. actinomycetemcomitans and P. gingivalis with reduction factors higher than 6.0. Diluted polyhexamethylene guanidine phosphate and chlorhexidine to 0.05% continued to display anti-bacterial activity and decreased titers of standard quality control, periopathogens to below 1.0 × 10(3) colony forming units/ml, albeit requiring prolonged exposure time. To achieve a bactericidal effect against S. mutans, both antiseptics at all concentrations required a longer exposure time. We found that a clinically-used 1% of polyhexamethylene guanidine phosphate concentration did not have activity against L. acidophilus. CONCLUSION: High RF of polyhexamethylene guanidine phosphate and retention of bactericidal effects, even at 0.05%, support the use of polyhexamethylene guanidine phosphate as a biocide with sufficient anti-microbial activity against periopathogens. Polyhexamethylene guanidine phosphate displayed bactericidal activity against periopathogens and S. mutans and could potentially be applied in the management of oral diseases.

Inflammatory markers and heart rate variability in women with coronary heart disease.

PURPOSE: Both heart rate variability (HRV) and inflammatory markers are carrying prognostic information in coronary heart disease (CHD), however, we know of no studies examining their relation in CHD. The aim of this study, therefore, was to assess the association between HRV and inflammatory activity, as reflected by the levels of interleukin-6 (IL-6), IL-1 receptor antagonist (IL-1ra) and C-reactive protein (CRP). SUBJECTS AND METHODS: Consecutive women patients who survived hospitalization for acute myocardial infarction, and/or underwent a percutaneous transluminal coronary angioplasty or a coronary artery bypass grafting were included and evaluated in a stable condition 1 year after the index events. An ambulatory 24-h ECG was recorded during normal activities. SDNN index (mean of the standard deviations of all normal to normal intervals for all 5-min segments of the entire recording) and the following frequency domain parameters were assessed: total power, high frequency (HF) power, low frequency (LF) power and very low frequency (VLF) power. Levels of high-sensitivity CRP were measured by nephelometry, IL-6 and IL-1ra concentrations were determined by enzyme immunoassay. RESULTS: Levels of IL-6 showed an inverse relation with HRV measures even after controlling for potential confounding factors. The P-values were 0.02, 0.04, 0.01, 0.03, 0.18 for the multivariate association with SDDN index, total power, VLF power, LF power and HF power respectively. In contrast, the inverse relationship between HRV measures and CRP or IL-1ra levels were weak and nonsignificant. Correlation coefficients for the relationship between IL-6 and HRV measures were both uni- and multivariately higher than for the relationship between HRV measures and any other factors evaluated in this study. CONCLUSION: Concentration of IL-6 showed a negative, independent association with HRV in women with CHD. Thus, increased inflammatory activity, as reflected by IL-6 levels, may represent a new auxiliary mechanism linking decreased HRV to poor prognosis in CHD.

Oral health and cardiovascular disease in Sweden.

OBJECTIVE: The purpose of the present study was to assess the relation between dental health and cardiovascular disease in an adult Swedish population. MATERIAL AND METHOD: A questionnaire was sent to 4811 randomly selected Swedes. It contained 52 questions about dental care habits, oral health, cardiovascular disease and their socio-economic situation. Odd ratios for all cardiovascular diseases (CVD) and the subgroup myocardial infarction, stroke and high blood pressure were calculated with a logistic regression model adjusted for age, gender, smoking, income, civil status and education. These ratios were calculated for subjects > or =41 years since few people suffer from CVD before this. RESULTS: The national questionnaire was answered by 2839 (59%) people between 20-84 years of age and, of them, 1577 were 41 years of age or more. We found a significant association between self-reported bleeding gums (odds ratio 1.60, p=0.0017), presence of dentures (odds ratio 1.57, p=0.0076) and known CVD, which has also been reported in international studies. However, no association between loose teeth, deep pockets and known CVD was detected. CONCLUSION: The results indicate that oral health and, especially gingival inflammation is associated with CVD.