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Epidemiologic data suggest a possible link between periodontal disease and cardiovascular disorders. In this study, patients with severe periodontitis who were treated with intensive periodontal therapy, as compared with standard community-based therapy, had improvement in flow-mediated dilatation, a measure of vascular endothelial function. The findings suggest that severe periodontal inflammation may promote vascular endothelial dysfunction. Patients with severe periodontitis who were treated with intensive periodontal therapy had improvement in flow-mediated dilatation, a measure of vascular endothelial function. Inflammation plays an important role in the pathogenesis of atherosclerosis, and low-grade chronic systemic inflammation has been shown to be linked to adverse cardiovascular outcomes. 1 The nature and source of the inflammation, however, remain unclear. Periodontitis, a very common chronic infection of the tissue surrounding the teeth, is associated with elevated levels of C-reactive protein (CRP) and other inflammatory biomarkers. 2 – 5 Cohort and case–control studies have shown that periodontitis is associated with endothelial dysfunction, 6 atherosclerosis, 7 and an increased risk of myocardial infarction and stroke. 8 In experimental models, periodontal pathogens have been shown to promote platelet aggregation, 9 foam-cell formation, 10 and the . . .

OBJECTIVE: Recent large randomized trials have linked adverse cardiovascular and cerebrovascular events with hypoglycemia. However, the integrated physiological and vascular biological mechanisms occurring during hypoglycemia have not been extensively examined. Therefore, the aim of this study was to determine whether 2 h of moderate clamped hypoglycemia could decrease fibrinolytic balance and activate pro-atherothrombotic mechanisms in individuals with type 1 diabetes and healthy individuals. RESEARCH DESIGN AND METHODS: Thirty-five healthy volunteers (19 male and 16 female subjects age 32 ± 2 years, BMI 26 ± 2 kg/m², A1C 5.1 ± 0.1%) and twenty-four with type 1 diabetes (12 male and 12 female subjects age 33 ± 3 years, BMI 24 ± 2 kg/m², A1C 7.7 ± 0.2%) were studied during either a 2-h hyperinsulinemic (9 pmol · kg⁻¹ · min⁻¹) euglycemic or hypoglycemic (2.9 ± 0.1 mmol/l) clamp or both protocols. Plasma glucose levels were normalized overnight in type 1 diabetic subjects prior to each study. RESULTS: Insulin levels were similar (602 ± 44 pmol/l) in all four protocols. Glycemia was equivalent in both euglycemic protocols (5.2 ± 0.1 mmol/l), and the level of hypoglycemia was also equivalent in both type 1 diabetic subjects and healthy control subjects (2.9 ± 0.1 mmol/l). Using repeated ANOVA, it was determined that plasminogen activator inhibitor (PAI-1), vascular cell adhesion molecule (VCAM), intercellular adhesion molecule (ICAM), E-selectin, P-selectin, interleukin-6 (IL-6), vascular endothelial growth factor (VEGF), and adiponectin responses were all significantly increased (P < 0.05) during the 2 h of hyperinsulinemic hypoglycemia as compared with euglycemia in healthy control subjects. All measures except PAI-1 were also found to be increased during hypoglycemia compared with euglycemia in type 1 diabetes. CONCLUSIONS: In summary, moderate hypoglycemia acutely increases circulating levels of PAI-1, VEGF, vascular adhesion molecules (VCAM, ICAM, E-selectin), IL-6, and markers of platelet activation (P-selectin) in individuals with type 1 diabetes and healthy individuals. We conclude that acute hypoglycemia can result in complex vascular effects including activation of prothrombotic, proinflammatory, and pro-atherogenic mechanisms in individuals with type 1 diabetes and healthy individuals.

Rationale The influence of COPD exacerbation on the endothelium is not completely understood. Circulating endothelial microparticles (EMPs) are membrane vesicles in circulating blood that are shed by activated or apoptotic endothelial cells. Objective To compare EMP numbers in stable COPD patients with those during and after exacerbation. Methods We examined the EMP numbers in 80 stable COPD patients, 27 patients with exacerbated COPD, and 20 healthy non-COPD volunteers. EMPs were defined as CD144+ MPs (VE-cadherin EMPs), CD31+/CD41− MPs (PECAM EMPs), CD146 MPs (MCAM EMPs) and CD62E+ EMPs (E-selectin EMPs) as analysed by FACS. Von Willebrand factor (vWF) expression was utilised to identify the origins of the EMPs. Results VE-cadherin, PECAM and E-selectin EMP numbers were significantly higher in the stable COPD patients than in the non-COPD volunteers, and they were significantly higher in the patients with exacerbated COPD than in the stable COPD patients. The majority of these increased EMPs were vWF-negative, indicating a pulmonary capillary origin. Baseline E-selectin EMP levels were significantly higher in COPD patients who experienced frequent exacerbations than in those who did not have frequent exacerbations (p<0.001). Twenty-eight days after the onset of exacerbation, E-selectin EMP levels returned to those observed in stable COPD patients, whereas PECAM EMP levels remained high. MCAM EMP numbers were not elevated in stable or exacerbated-COPD patients. Conclusions Endothelial damage, mainly in pulmonary capillaries, occurs during exacerbation and continues even after clinical symptoms disappear. Higher baseline E-selectin EMP levels may indicate COPD patients who are susceptible to exacerbation.

An increasingly recognized prognostic factor for out-of-hospital-cardiac-arrest (OHCA) patients is the ischemia-reperfusion injury after restored blood circulation. Endothelial injury is common in patients resuscitated from cardiac arrest and is associated with poor outcome. This study was designed to investigate if iloprost infusion, a prostacyclin analogue, reduces endothelial damage in OHCA patients. 50 patients were randomized in a placebo controlled double-blinded trial and allocated 1:2 to 48-hours iloprost infusion, (1 ng/kg/min) or placebo (saline infusion). Endothelial biomarkers (soluble thrombomodulin (sTM), sE-selectin, syndecan-1, soluble vascular endothelial growth factor (sVEGF), vascular endothelial cadherine (VEcad), nucleosomes) and sympathoadrenal activation (epinephrine/norepinephrine) from baseline to 48 and 96-hours were evaluated. Iloprost infusion did not influence endothelial biomarkers by the 48-hour endpoint. A rebound effect was observed with higher biomarker plasma values in the iloprost group (sTM p=0.02; Syndecan p=0.004; nucleosomes p<0.001; VEcad p<0.03) after 96-hours. There was a significant difference in 180-day mortality in favor of placebo. There was no difference regarding total adverse events between groups (p=0.73). Two patients were withdrawn in the iloprost group due to hypotension. The administration of low-dose iloprost (1ng/kg/min) to OHCA patients did not significantly influence endothelial biomarkers as measured by the 48- hour endpoint. A rebound effect was however observed in the 96-hour statistical model, with increasing endothelial biomarker levels after cessation of the iloprost-infusion.

Aims/hypothesisWe compared the associations of circulating biomarkers of inflammation, endothelial and adipocyte dysfunction and coagulation with incident diabetes in the placebo, lifestyle and metformin intervention arms of the Diabetes Prevention Program, a randomised clinical trial, to determine whether reported associations in general populations are reproduced in individuals with impaired glucose tolerance, and whether these associations are independent of traditional diabetes risk factors. We further investigated whether biomarker–incident diabetes associations are influenced by interventions that alter pathophysiology, biomarker concentrations and rates of incident diabetes.MethodsThe Diabetes Prevention Program randomised 3234 individuals with impaired glucose tolerance into placebo, metformin (850 mg twice daily) and intensive lifestyle groups and showed that metformin and lifestyle reduced incident diabetes by 31% and 58%, respectively compared with placebo over an average follow-up period of 3.2 years. For this study, we measured adiponectin, leptin, tissue plasminogen activator (as a surrogate for plasminogen activator inhibitor 1), high-sensitivity C-reactive protein, IL-6, monocyte chemotactic protein 1, fibrinogen, E-selectin and intercellular adhesion molecule 1 at baseline and at 1 year by specific immunoassays. Traditional diabetes risk factors were defined as family history, HDL-cholesterol, triacylglycerol, BMI, fasting and 2 h glucose, HbA1c, systolic blood pressure, inverse of fasting insulin and insulinogenic index. Cox proportional hazard models were used to assess the effects of each biomarker on the development of diabetes assessed semi-annually and the effects of covariates on these.ResultsE-selectin, (HR 1.19 [95% CI 1.06, 1.34]), adiponectin (0.84 [0.71, 0.99]) and tissue plasminogen activator (1.13 [1.03, 1.24]) were associated with incident diabetes in the placebo group, independent of diabetes risk factors. Only the association between adiponectin and diabetes was maintained in the lifestyle (0.69 [0.52, 0.92]) and metformin groups (0.79 [0.66, 0.94]). E-selectin was not related to diabetes development in either lifestyle or metformin groups. A novel association appeared for change in IL-6 in the metformin group (1.09 [1.021, 1.173]) and for baseline leptin in the lifestyle groups (1.31 [1.06, 1.63]).Conclusions/interpretationThese findings clarify associations between an extensive group of biomarkers and incident diabetes in a multi-ethnic cohort with impaired glucose tolerance, the effects of diabetes risk factors on these, and demonstrate differential modification of associations by interventions. They strengthen evidence linking adiponectin to diabetes development, and argue against a central role for endothelial dysfunction. The findings have implications for the pathophysiology of diabetes development and its prevention.

Background. Beside the lipid-lowering effect, statins slow the progression of atherosclerosis by exerting anti-inflammatory and platelet inhibiting effects. We investigated whether platelet inhibition by simvastatin correlates with the statin effects on lipid lowering, inflammation, oxidative stress, and endothelial and platelet activation. Methods. In hypercholesterolemic patients allocated to diet (n=20) or a 2-month treatment with diet plus 40 mg simvastatin (n=25), we evaluated platelet aggregating responses to ADP, collagen, and arachidonic acid (AA), the effect of aspirin on AA-induced aggregation, pro- and anti-inflammatory and atherogenic mediators (IL-1β, -5, -6, -7, -8, -9, -10, -12, and -13, IFN-γ, IP-10, Eotaxin, and sRAGE), markers of endothelium (sE-selectin, VEGF, and MCP-1) and platelet activation (sP-selectin, sCD-40L, RANTES, and PDGF-bb), and oxidative stress (8-OH-2’-deoxyguanosine). Results. After treatment, beside the improvement of lipid profile, we observed the following: a reduction of platelet aggregation to ADP (p=0.0001), collagen (p=0.0001), AA (p=0.003); an increased antiaggregating effect of aspirin in the presence of AA (p=0.0001); a reduction of circulating levels of IL-6 (p=0.0034), IL-13 (p<0.0001), IFN-γ (p<0.0001), VEGF (p<0.0001), sE-selectin (p<0.0001), sCD-40L (p<0.0001), sP-selectin (p=0.003), and 8-OH-2’-deoxyguanosine (p<0.0001); an increase of IL-10 and sRAGEs (p=0.0001 for both). LDL-cholesterol levels (i) positively correlated with IL-6, IFN-γ, E-selectin, sCD-40L, 8-OH-2’-deoxyguanosine, platelet aggregation to ADP, collagen, AA, and aspirin IC-50 and (ii) negatively correlated with IL-10 and sRAGE. In multiple regression analyses, LDL-cholesterol was the strongest predictor for most parameters of platelet reactivity. Conclusion. In primary hypercholesterolemia, simvastatin treatment reduced platelet activation and subclinical inflammation and improved endothelial dysfunction. LDL-cholesterol levels were the major correlate of platelet reactivity; however, other effects of statins may contribute to reducing the progression of atherosclerosis.

Aims/hypothesis Low-grade inflammation and endothelial dysfunction may play a role in the pathogenesis of type 2 diabetes and cardiovascular disease. We evaluated whether a diet high in fatty fish, bilberries and wholegrain products (Healthy Diet) improves biomarkers reflecting inflammation and endothelial dysfunction in individuals with impaired glucose metabolism. Methods We recruited individuals with impaired glucose metabolism and features of the metabolic syndrome into a 12 week, parallel design, dietary intervention trial conducted at the Department of Clinical Nutrition, University of Eastern Finland (Kuopio, Finland). Randomisation was performed by matching according to sex and medians of age, BMI and fasting plasma glucose of the study population at screening. The primary endpoint in the present study was the change in plasma inflammatory markers and the measurements were performed blinded to group assignment. High-sensitivity (hs) C-reactive protein (CRP) and E-selectin responses were also analysed separately in participants not using statins ( n  = 76). Results Altogether, 131 individuals were assigned to either the Healthy Diet ( n  = 44), a whole-grain-enriched diet (WGED) ( n  = 42) or a control ( n  = 45) diet, and 104 participants (mean ± SD: age 59 ± 7 years; BMI 31.1 ± 3.5 kg/m 2 ) who had completed the study, were analysed (Healthy Diet n  = 36, WGED n  = 34 and control diet n  = 34). Plasma E-selectin decreased only in the Healthy Diet group. This occurred in all group participants ( p  < 0.05) and also after excluding participants using statins ( p  < 0.05). Plasma hsCRP levels decreased in the Healthy Diet (median −17%, p  < 0.05) and WGED (median −27%, p  < 0.01) groups in participants not using statins. Controlling for confounding factors, including BMI or insulin sensitivity, did not alter the results. A greater increase in plasma concentration of very-long-chain n -3 fatty acids and in the intake of fibre during the study was associated with a greater decrease in plasma E-selectin ( p  < 0.05). The intake of test breads consumed during the Healthy Diet and WGED interventions was inversely associated with the change in hsCRP levels ( p  < 0.001). Conclusions/interpretation Our results suggest that the combined effect of fatty fish, bilberries and wholegrain products may improve endothelial dysfunction and inflammation in overweight and obese individuals at high risk of developing diabetes. Trial registration: ClinicalTrials.gov NCT00573781 Funding: The study was funded by the Academy of Finland (117844 and 118590 [to M. Uusitupa]; 131460 [to K. Poutanen]; 130469 [to H. Mykkänen] and 131593 [to V. D. F. de Mello]); the Kuopio University Hospital (5106, 5168, 5254 [to M. Uusitupa]); the Finnish Diabetes Research Foundation; the Sigrid Juselius Foundation; the Nordic Centre of Excellence on ‘Systems biology in controlled dietary interventions and cohort studies’ (SYSDIET; 070014); and the European Commission in the Communities 6th Framework Programme, Project HEALTHGRAIN (FOOD-CT-2005-514008).

Sympathoadrenal activation and endothelial damage are hallmarks of acute critical illness. This study investigated their association and predictive value in patients resuscitated from out-of-hospital cardiac arrest (OHCA). Post-hoc analysis of patients included at a single site in The Targeted Temperature Management at 33 degrees versus 36 degrees after Cardiac Arrest (TTM) trial. The main study reported similar outcomes with targeting 33 versus 36 degrees. TTM main study ClinicalTrials.gov: NCT01020916. One hundred sixty three patients resuscitated from OHCA were included at a single site ICU. Blood was sampled a median 135 min (Inter Quartile Range (IQR) 103-169) after OHCA. Plasma catecholamines (adrenaline, noradrenaline) and serum endothelial biomarkers (syndecan-1, thrombomodulin, sE-selectin, sVE-cadherin) were measured at admission (immediately after randomization). We had access to data on demography, medical history, characteristics of the OHCA, patients and 180-day outcome. Adrenaline and noradrenaline correlated positively with syndecan-1 and thrombomodulin i.e., biomarkers reflecting endothelial damage (both p<0.05). Overall 180-day mortality was 35%. By Cox analyses, plasma adrenaline, serum sE-selectin, reflecting endothelial cell activation, and thrombomodulin levels predicted mortality. However, thrombomodulin was the only biomarker independently associated with mortality after adjusting for gender, age, rhythm (shockable vs. non-shockable), OHCA to return of spontaneous circulation (ROSC) time, shock at admission and ST elevation myocardial infarction (30-day Hazards Ratio 1.71 (IQR 1.05-2.77), p=0.031 and 180-day Hazards Ratio 1.65 (IQR 1.03-2.65), p=0.037 for 2-fold higher thrombomodulin levels). Circulating catecholamines and endothelial damage were intercorrelated and predicted increased mortality. Interventions aiming at protecting and/or restoring the endothelium may be beneficial in OHCA patients.

Objective Almonds reduce cardiovascular disease risk via cholesterol reduction, anti-inflammation, glucoregulation, and antioxidation. The objective of this randomized, controlled, cross-over trial was to determine whether the addition of 85 g almonds daily to a National Cholesterol Education Program (NCEP) Step 1 diet (ALM) for 6 weeks would improve vascular function and inflammation in patients with coronary artery disease (CAD). Research design and methods A randomized, controlled, crossover trial was conducted in Boston, MA to test whether as compared to a control NCEP Step 1 diet absent nuts (CON), incorporation of almonds (85 g/day) into the CON diet (ALM) would improve vascular function and inflammation. The study duration was 22 weeks including a 6-weeks run-in period, two 6-weeks intervention phases, and a 4-weeks washout period between the intervention phases. A total of 45 CAD patients (27 F/18 M, 45–77 y, BMI = 20-41 kg/m 2 ) completed the study. Drug therapies used by patients were stable throughout the duration of the trial. Results The addition of almonds to the CON diet increased plasma α-tocopherol status by a mean of 5.8 %, reflecting patient compliance (P ≤0.05). However, the ALM diet did not alter vascular function assessed by measures of flow-mediated dilation, peripheral arterial tonometry, and pulse wave velocity. Further, the ALM diet did not significantly modify the serum lipid profile, blood pressure, C-reactive protein, tumor necrosis factor-α or E-selectin. The ALM diet tended to decrease vascular cell adhesion molecule-1 by 5.3 % ( P  = 0.064) and increase urinary nitric oxide by 17.5 % ( P  = 0.112). The ALM intervention improved the overall quality of the diet by increasing calcium, magnesium, choline, and fiber intakes above the Estimated Average Requirement (EAR) or Recommended Dietary Allowance (RDA). Conclusions Thus, the addition of almonds to a NECP Step 1 diet did not significantly impact vascular function, lipid profile or systematic inflammation in CAD patients receiving good medical care and polypharmacy therapies but did improve diet quality without any untoward effect. Trial registration The trial was registered with the ClinicalTrials.Gov with the identifier: NCT00782015 .

Background Low back pain (LBP) is a common musculoskeletal condition and a major cause of disability worldwide. Previous studies have found associations of biomarkers with pain and pain-related disability in LBP patients. This study aimed to explore the association between serum biomarkers and pain and disability in patients with acute or subacute axial LBP. Methods This study was ancillary to a parent randomized controlled trial. Enrolled participants were randomized into three intervention groups: one of two types of spinal manipulation or medical care. In the parent study, 107 adults who experienced a new episode of LBP within 3 months prior to enrollment were recruited. For this study, 90 of these 107 participants consented to have blood samples obtained, which were drawn immediately before the beginning of treatment. Seven biomarkers were chosen based on previous literature and analyzed. Clinical outcomes were pain and Oswestry Disability Index (ODI) evaluated at baseline and 4 weeks. Spearman’s |r| was used to study the association of initial levels of each biomarker with pain and ODI scores at baseline and with changes in outcome scores from baseline to 4 weeks (end of treatment) within each intervention group. Results At baseline, 4 of 7 biomarkers had an association with pain that was |r| ≥ .20: neuropeptide Y (NPY) ( r  = 0.23, p  = .028), E-Selectin ( r  = 0.22, p  = .043), vitamin D (( r  = − 0.32, p  = .002), and c-reactive protein (CRP) ( r  = 0.37, p  = .001). No baseline biomarker had an association with disability that was |r| ≥ 0.20. For the correlations of baseline biomarkers with 4-week change in outcomes, vitamin D showed a correlation with change in disability and/or pain (|r| ≥ 0.20, p  > .05) in manipulation-related groups, while CRP, NPY, and E-selectin along with TNFα, Substance P and RANTES showed at least one correlation with change in pain or disability (|r| ≥ 0.20, p > .05) in at least one of the treatment groups. Conclusions In 90 LBP patients, the analyzed biomarkers, especially vitamin D, represent a small set of potential candidates for further research aimed at individualizing patient care. Overall, the associations investigated in the current study are an initial step in identifying the direct mechanisms of LBP and predicting outcomes of manipulation-related treatments or medical care. Trial registration ClinicalTrials.gov Identifier: NCT01211613, Date of Registration: September 29, 2010, https://clinicaltrials.gov/ct2/show/NCT01211613?term=schneider&cond=Low+Back+Pain&cntry=US&state=US%3APA&draw=2&rank=1