Periodontitis is a common infectious disease associated with increased risk for ischemic stroke though presently unclear mechanisms. In a case-control study, we investigated salivary levels of four periodontal pathogens, as well as systemic and local inflammatory markers. The population comprised 98 patients with acute ischemic stroke (mean ± SD, 68.2 ± 9.7 yrs; 45.9% women) and 100 healthy controls (69.1 ± 5.2 yrs; 47.0% women). Patients were more often edentulous and had fewer teeth than controls (13.8 ± 10.8 versus 16.6 ± 10.1). After adjusting for stroke risk factors and number of teeth, controls had higher saliva matrix metalloproteinase-8 (MMP-8), myeloperoxidase (MPO), IL-1β, Aggregatibacter actinomycetemcomitans, and serum LPS activity levels. Patients had higher serum MMP-8 and MPO, and they were more often qPCR-positive for A. actinomycetemcomitans (37.9% versus 19.0%) and for ≥3 periodontopathic species combined (50.0% versus 33.0%). We conclude that controls more often had evidence of current periodontal infection with higher periodontal pathogen amount, endotoxemia, local inflammation and tissue destruction. Stroke patients more often had evidence of end-stage periodontitis with edentulism and missing teeth. They were more often carriers of several periodontopathic pathogens in saliva, especially A. actinomycetemcomitans. Additionally, inflammatory burden may contribute to high systemic inflammation associated with elevated stroke susceptibility.

Matrix metalloproteinase (MMP)-9 is crucial in atherosclerotic plaque rupture and tissue remodeling after a cardiac event. The balance between MMP-9 and endogenous inhibitor, tissue inhibitors of matrix metalloproteinase 1 (TIMP-1), is important in acute coronary syndrome (ACS). This is an age- and gender-matched case-control study of ACS (N = 669). Patients (45.7%) were resampled after recovery, and all were followed up for 6 years. The molecular forms of MMP-9 were investigated by gelatin zymography. Diagnostically, MMP-9 and the MMP-9/TIMP-1 molar ratio were associated with ACS (OR 5.81, 95% CI 2.65–12.76, and 4.96, 2.37–10.38). The MMP-9 concentrations decreased 49% during recovery (p < 0.001). The largest decrease of these biomarkers between acute and recovery phase (ΔMMP-9) protected the patients from major adverse cardiac events, especially the non-fatal events. The fatal events were associated with in vitro activatable MMP-9 levels (p = 0.028). Serum MMP-9 and the MMP-9/TIMP-1 molar ratio may be valuable in ACS diagnosis and prognosis. High serum MMP-9 activation potential is associated with poor cardiovascular outcome.Electronic supplementary materialThe online version of this article (10.1007/s12265-018-9789-x) contains supplementary material, which is available to authorized users.

MMP-8, MMP-9, TIMP-1and MPO are valuable biomarkers for both ACS and periodontitis, but the selection of sample material is crucial; serum is suitable for ACS and saliva for periodontal diagnostic aid.

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-DNAhybridization, 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.

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 (allcause 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.

Background Smoking is a risk factor for periodontal disease because of its complex impact on the inflammatory response in the periodontium. We investigated the effect of smoking on salivary periodontal biomarkers, matrix metalloproteinase (MMP)‐8, MMP‐9, tissue inhibitor of metalloproteinase (TIMP)‐1 and myeloperoxidase (MPO). Methods Saliva biomarkers were analyzed in the Parogene population (n = 480) comprising a random cohort of patients that have undergone coronary angiography and oral examination. The effect of time since cessation and pack years of smoking on biomarkers were investigated. Results Saliva MMP‐8, MMP‐9, TIMP‐1, and MPO concentrations distinguished periodontitis patients significantly from patients without periodontitis. When the time since cessation was considered, the area‐under‐the‐curve values (p‐value) for periodontitis were 0.76 (<0.001), 0.74 (<0.001), 0.70 (<0.001), and 0.76 (<0.001), respectively. Adding information about smoking habits in the models improved slightly the sensitivities of all biomarkers. In logistic regression model saliva, MMP‐8 was mainly affected by pack years of smoking, whereas saliva MMP‐9, TIMP‐1, and MPO were mostly affected by time since cessation, especially if smoking currently or quit recently (<1 year ago). Conclusion Smoking confounds the salivary diagnostics of periodontitis and should be considered when interpreting the results obtained by potential diagnostic tests.

Background: Smoking has been perceived to increase the levels of carcinogenic and inflammatory mediators thereby promoting presumably malignant and proinflammatory tissue destruction via activating proteolytic enzymes such as matrix metalloproteinases (MMPs) and their regulators. We studied the effect of smoking on the diagnostic ability of serum MMP-8-IFMA and TIMP-1-ELISA analysis to recognize patients with acute coronary syndrome (ACS). Methods: The case-control population (n=605) comprised 291 patients with diagnosed acute myocardial infarction (AMI) or unstable angina pectoris (UAP) and 314 healthy control individuals. The case and the control group included 55 and 66 smoking subjects, respectively. Results: Smoking increased the MMP-8, but not the TIMP-1, concentration in both the control and the AMI group. MMP-8 concentration, and consequently MMP-8/TIMP-1, distinguished the cases from the controls accurately in the ROC analysis, but smoking decreased the AUCs in every category. The MMP-8 concentration produced an AUC (95% CI, p-value) for ACS of 0.771 (0.723-0.818, p<0.001) and 0.684 (0.581-0.787, p=0.001) for non-smokers and smokers, respectively. Similarly, the multivariate logistic regression model indicated that smoking decreased the association of MMP-8 with ACS. The OR (95% CI, p-value) of MMP-8 for ACS was 8.1 (per ng/ml log-transformed unit increase, 5.0-13.1, p<0.001) and 2.8 (1.1-7.0, p=0.025) for non-smokers and smokers, respectively. Conclusions: One of the most important risk factors for ACS, smoking, decreases the diagnostic ability of MMP-8 concentration and MMP-8/TIMP-1 ratio. This must be taken account if these serum determinations are used as biomarkers of the risk for cardiovascular diseases.

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