Association of peptidoglycan recognition protein 1 to post-myocardial infarction and periodontal inflammation : A subgroup report from the PAROKRANK (Periodontal Disease and the Relation to Myocardial Infarction) study

Background: Peptidoglycan recognition protein 1 (PGLYRP1) is an antimicrobial and proinflammatory innate immunity protein activated during infections. We aimed to investigate whether PGYLRP1 and associated molecules of the immune response in saliva is a cumulative outcome result of both MI and periodontal inflammation. Methods and Results: Two hundred patients with MI and another 200 matched non-MI controls were included. A full-mouthexamination was conducted to assess periodontal inflammation and collection of stimulated saliva was performed 6 to 10 weeks after the first MI. PGLYRP1, triggering receptor expressed on myeloid cells 1 (TREM-1), interleukin-1 beta (IL-1 beta) were analyzed by ELISA. Matrix metalloproteinase (MMP)-8 levels were determined by IFMA. Compared to controls, MI patients showed higher salivary PGLYRP1, but not TRIM-1 levels. The difference in PGLYRP1 levels remained after adjustment for covariates. In MI patients, the PGLYRP1 levels positively correlated with BOP and PPD 4 to 5 mm. Among non-MI subjects, the levels of PGLYRP1 correlated positively and significantly with BOP and total PPD. Salivary PGLYRP1 concentrations also showed strong positive correlations with levels of TRIM-1, IL-1 beta and MM P-8. In multivariate linear regression analysis, in MI patients, BOP and former smokingstatus displayed an association with salivary PGLYRP1 concentration. Conclusion: MI patients showed higher salivary PGLYRP1 levels than healthy controls, also after adjusting for smoking, sex, age and periodontal health status. Salivary levels of PGLYRP1 may reflect the overall inflammatory burden to chronic bacterial exposure, possibly underpinning the observed associations between periodontitis and exposure with MI.Peer reviewe

How representative of a general type 2 diabetes population are patients included in cardiovascular outcome trials with SGLT2 inhibitors? A large European observational study

Aims: Enrollment criteria vary substantially among cardiovascular outcome trials (CVOTs) of sodium-glucose cotransporter-2 inhibitors (SGLT-2is), which impacts the relationship between a trial population and the general type 2 diabetes (T2D) population. The aim of this study was to evaluate the representativeness of four SGLT-2i CVOTs of a general T2D population. Methods: T2D patients from Germany, The Netherlands, Norway and Sweden were included in the study. Given the available data per country, key inclusion and exclusion criteria were defined by diagnoses, procedures and drug treatments to facilitate comparability among countries. Representativeness was determined by dividing the number of patients fulfilling the key enrolment criteria of each CVOT (CANVAS, DECLARE-TIMI 58, EMPA-REG OUTCOME, VERTIS-CV) by the total T2D population. Results: In 2015, a total T2D population of 803 836 patients was identified in Germany (n = 239 485), in The Netherlands (n = 36 213), in Norway (n = 149 782) and in Sweden (n = 378 356). These populations showed a 25% to 44% cardiovascular (CV) disease baseline prevalence and high CV-preventive drug use (>80%). The general T2D population had less prevalent CV disease and patients were slightly older than those included in the CVOTs. The DECLARE-TIMI 58 trial had the highest representativeness, 59% compared to the general T2D population, and this representativeness was almost 2-, 3- and 4-fold higher compared to the CANVAS (34%), EMPA-REG OUTCOME (21%) and VERTIS-CV (17%) trials, respectively. Conclusions: In large T2D populations within Europe, consistent patterns of representativeness of CVOTs were found when applying the main enrolment criteria. The DECLARE-TMI 58 trial had the highest representativeness, indicating that it included and examined patients who are most representative of the general T2D patients in the studied countries

Prevalence, outcomes and costs of a contemporary, multinational population with heart failure.

OBJECTIVE Digital healthcare systems could provide insights into the global prevalence of heart failure (HF). We designed the CardioRenal and Metabolic disease (CaReMe) HF study to estimate the prevalence, key clinical adverse outcomes and costs of HF across 11 countries. METHODS Individual level data from a contemporary cohort of 6 29 624 patients with diagnosed HF was obtained from digital healthcare systems in participating countries using a prespecified, common study plan, and summarised using a random effects meta-analysis. A broad definition of HF (any registered HF diagnosis) and a strict definition (history of hospitalisation for HF) were used. Event rates were reported per 100 patient years. Cumulative hospital care costs per patient were calculated for a period of up to 5 years. RESULTS The prevalence of HF was 2.01% (95% CI 1.65 to 2.36) and 1.05% (0.85 to 1.25) according to the broad and strict definitions, respectively. In patients with HF (broad definition), mean age was 75.2 years (95% CI 74.0 to 76.4), 48.8% (40.9-56.8%) had ischaemic heart disease and 34.5% (29.4-39.6%) had diabetes. In 51 442 patients with a recorded ejection fraction (EF), 39.1% (30.3-47.8%) had a reduced, 18.8% (13.5-24.0%) had a mildly reduced and 42.1% (31.5-52.8%) had a preserved left ventricular EF. In 1 69 518 patients with recorded estimated glomerular filtration rate, 49% had chronic kidney disease (CKD) stages III-V. Event rates were highest for cardiorenal disease (HF or CKD) and all cause mortality (19.3 (95% CI 11.3 to 27.1) and 13.1 (11.1 to 15.1), respectively), and lower for myocardial infarction, stroke and peripheral artery disease. Hospital care costs were highest for cardiorenal diseases. CONCLUSIONS We estimate that 1-2% of the contemporary adult population has HF. These individuals are at significant risk of adverse outcomes and associated costs, predominantly driven by hospitalisations for HF or CKD. There is considerable public health potential in understanding the contemporary burden of HF and the importance of optimising its management

Salivary Matrix Metalloproteinase-8 and-9 and Myeloperoxidase in Relation to Coronary Heart and Periodontal Diseases : A Subgroup Report from the PAROKRANK Study (Periodontitis and Its Relation to Coronary Artery Disease)

Background and Objective Matrix metalloproteinase (MMP) -8, -9 and myeloperoxidase (MPO) are inflammatory mediators. The potential associations between MMP-8, -9, MPO and their abilities to reflect cardiovascular risk remains to be evaluated in saliva. The objective of this study was to investigate the levels and associations of salivary MMP-8, -9, MPO and tissue inhibitors of metalloproteinase (TIMP)-1 in myocardial infarction (MI) patients and controls with or without periodontitis. Materials and Methods 200 patients with a first MI admitted to coronary care units in Sweden from May 2010 to December 2011 and 200 controls matched for age, gender, residential area and without previous MI were included. Dental examination and saliva sample collection was performed 6-10 weeks after the MI in patients and at baseline in controls. The biomarkers MMP -8, -9, MPO and TIMP-1 were analyzed by time-resolved immunofluorescence assay (IFMA), Western blot and Enzyme-Linked ImmunoSorbent Assay (ELISA). Results After compensation for gingivitis, gingival pockets and smoking, the mean salivary levels of MMP-8 (543 vs 440 ng/mL, p = 0.003) and MPO (1899 vs 1637 ng/mL, p = 0.02) were higher in non-MI subjects compared to MI patients. MMP-8, -9 and MPO correlated positively with clinical signs of gingival/periodontal inflammation while TIMP-1 correlated mainly negatively with these signs. The levels of latent and active forms of MMP-8 did not differ between the MI and non-MI groups. Additionally, MMP-8, MPO levels and MMP-8/TIMP-1 ratio were significantly higher in men compared to women with MI. Conclusions This study shows that salivary levels of the analyzed biomarkers are associated with periodontal status. However, these biomarkers could not differentiate between patients with or without a MI. These findings illustrate the importance to consider the influence of oral conditions when analyzing levels of inflammatory salivary biomarkers.Peer reviewe

Risk of cardiovascular events and death associated with initiation of SGLT2 inhibitors compared with DPP-4 inhibitors:an analysis from the CVD-REAL 2 multinational cohort study

Background Cardiovascular outcome trials have shown cardiovascular benefit with sodium-glucose co-transporter-2 (SGLT2) inhibitors in patients with type 2 diabetes, whereas dipeptidyl peptidase-4 (DPP-4) inhibitors have not shown an effect. We aimed to address knowledge gaps regarding the comparative effectiveness of SGLT2 inhibitor use in clinical practice (with DPP-4 inhibitor use as an active comparator) across a range of cardiovascular risks and in diverse geographical settings. Methods In this comparative cohort study, we used data from clinical practice from 13 countries in the Asia-Pacific, Middle East, European, and North American regions to assess the risk of cardiovascular events and death in adult patients with type 2 diabetes newly initiated on SGLT2 inhibitors compared with those newly initiated on DPP-4 inhibitors. De-identified health records were used to select patients who were initiated on these drug classes between Dec 1, 2012, and May 1, 2016, with follow-up until Dec 31, 2014, to Nov 30, 2017 (full range; dates varied by country). Non-parsimonious propensity scores for SGLT2 inhibitor initiation were developed for each country and patients who were initiated on an SGLT2 inhibitor were matched with those who were initiated on a DPP-4 inhibitor in a 1:1 ratio. Outcomes assessed were hospitalisation for heart failure, all-cause death, myocardial infarction, and stroke. Hazard ratios (HRs) were estimated by country and then pooled in a weighted meta-analysis. Findings Following propensity score matching, 193 124 new users of SGLT2 inhibitors and 193 124 new users of DPP-4 inhibitors were included in the study population. Participants had a mean age of 58 years (SD 12.2), 170 335 (44.1%) of 386 248 were women, and 111933 (30.1%) of 372 262 had established cardiovascular disease. Initiation of an SGLT2 inhibitor versus a DPP-4 inhibitor was associated with substantially lower risks of hospitalisation for heart failure (HR 0.69, 95% CI 0. 61-0. 77; p Interpretation In this large, international, observational study, initiation of SGLT2 inhibitors versus DPP-4 inhibitors was associated with lower risks of heart failure, death, myocardial infarction, and stroke, providing further support for the cardiovascular benefits associated with use of SGLT2 inhibitors in patients with type 2 diabetes. Copyright (C) 2020 Elsevier Ltd. All rights reserved

Lower Risk of Heart Failure and Death in Patients Initiated on Sodium-Glucose Cotransporter-2 Inhibitors Versus Other Glucose-Lowering DrugsClinical Perspective: The CVD-REAL Study (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors)

Reduction in cardiovascular death and hospitalization for heart failure (HHF) was recently reported with the sodium-glucose cotransporter-2 inhibitor (SGLT-2i) empagliflozin in patients with type 2 diabetes mellitus who have atherosclerotic cardiovascular disease. We compared HHF and death in patients newly initiated on any SGLT-2i versus other glucose-lowering drugs in 6 countries to determine if these benefits are seen in real-world practice and across SGLT-2i class

Cardiovascular outcomes with sodium-glucose cotransporter-2 inhibitors vs other glucose-lowering drugs in 13 countries across three continents: analysis of CVD-REAL data

BACKGROUND: Randomized, controlled cardiovascular outcome trials may not be fully representative of the management of patients with type 2 diabetes across different geographic regions. We conducted analyses of data from the multinational CVD-REAL consortium to determine the association between initiation of sodium–glucose cotransporter-2 inhibitors (SGLT-2i) and cardiovascular outcomes, including subgroup analyses based on patient characteristics. METHODS: De-identified health records from 13 countries across three continents were used to identify patients newly-initiated on SGLT-2i or other glucose-lowering drugs (oGLDs). Propensity scores for SGLT-2i initiation were developed in each country, with 1:1 matching for oGLD initiation. In the matched groups hazard ratios (HRs) for hospitalization for heart failure (HHF), all-cause death (ACD), the composite of HHF or ACD, myocardial infarction (MI) and stroke were estimated by country, and pooled using a weighted meta-analysis. Multiple subgroup analyses were conducted across patient demographic and clinical characteristics to examine any heterogeneity in treatment effects. RESULTS: Following matching, 440,599 new users of SGLT-2i and oGLDs were included in each group. Mean follow-up time was 396 days for SGLT-2i initiation and 406 days for oGLDs initiation. SGLT-2i initiation was associated with a lower risk of HHF (HR: 0.66, 95%CI 0.58–0.75; p < 0.001), ACD (HR: 0.52, 95%CI 0.45–0.60; p < 0.001), the composite of HHF or ACD (HR: 0.60, 95%CI 0.53–0.68; p < 0.001), MI (HR: 0.85, 95%CI 0.78–0.92; p < 0.001), and stroke (HR: 0.78, 95%CI 0.72–0.85; p < 0.001); regardless of patient characteristics, including established cardiovascular disease, or geographic region. CONCLUSIONS: This CVD-REAL study extends the findings from the SGLT-2i clinical trials to the broader setting of an ethnically and geographically diverse population, and across multiple subgroups. Trial registration NCT02993614 SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s12933-021-01345-z

Diabetes mellitus, glucose abnormalities and acute coronary syndromes : Studies on prevalence, risk and impact of treatment

Background: Persons with diabetes mellitus and impaired glucose tolerance are at increased risk for cardiovascular disease.The prevalence of known diabetes among patients with acute myocardial infarction, about 20%, is expected to increase in the coming decades. Despite recent improvements in the overall management of cardiovascular disease, the mortality after myocardial infarction in patients with diabetes remains high. Aims: This thesis analyses the relation between glucose abnormalities and acute coronary syndromes focus on 1 .Risk factors and the importance of insulin based meticulous metabolic control in patients with diabetes and acute myocardial infarction 2. The actual prevalence of glucose abnormalities in patients with acute myocardial infarction 3. The use of evidenced based treatment in patients with diabetes and acute myocardial infarction 4. The effect of early revascularisation in patients with diabetes and with unstable coronary artery disease. Blood glucose as a risk factor: In the prospective randomised DIGAMI study including 620 patients with acute myocardial infarction, insulin-based intense metabolic care initiated by a 24 hours insulin-glucose infusion followed by at least three months of subcutaneous multidose insulin treatment, reduced the long-term mortality with almost 30%. The most important risk factors for long-term mortality were high age, previous heart failure, and the glucometabolic state at admission. Besides established risk factors poor metabolic control at admission indicated a worse prognosis, which was attenuated by intense insulin treatment. Plasma glucose was examined at admission in 197 patients with acute myocardial infarction without previously known diabetes mellitus. During two years of follow up 40% had a major cardiovascular event. Independent risk factors for such event were a high admission plasma glucose, previous heart failure and high age. Thus, even among non-diabetic patients with acute myocardial infarction a high glucose level at admission identifies patients with worse prognosis. Glucose abnormalities and acute coronary syndromes: In 181 non-diabetic patients with acute myocardial infarction, who were examined with oral glucose tolerance tests during their initial hospitalisation, 3 1% fulfilled established criteria for diabetes mellitus while 35% had impaired glucose tolerance. These proportions were similar three months later, 25% and 40% respectively. Thus, previously undetected diabetes mellitus and pre diabetes were surprisingly common. Diabetes and acute coronary syndromes: In RIKS-HIA, (Swedish Register of Information and Knowledge about Swedish Care Units) the mean prevalence of diabetes was 20% among 25 632 persons below the age of 80 years who were hospitalised 1995-98 with an acute myocardial infarction. Diabetes was a strong independent predictor for mortality during the first year. Evidenced based treatment was similarly efficacious in patients with and without diabetes, however, significantly less utilised in the diabetic cohort. Thus, there are potentials to improve the prognosis of diabetic patients with myocardial infarction simply by better use of standard treatment. In the FRISC 2 trial, on the effect of early revascularisation in patients with unstable coronary artery disease, 299 (12%) of the patients had a previously diagnosed diabetes mellitus. The primary endpoint, death or a non-fatal reinfarction during one year of follow up was more prevalent among patients with diabetes. The relative improvement in prognosis induced by early revascularisation was similar in both groups. After adjustment for risk factors including number of diseased coronary arteries, diabetes remained as the strongest predictor for an unfavourable outcome. Thus, factors beyond the extent of coronary artery atherosclerosis seems to be of importance for the outcome in patients with diabetes mellitus and unstable coronary artery disease. Conclusions: Diabetes and pre-diabetes are considerably more common among patients with acute myocardial infarction than previously expected. Diabetic patient still have a worse outcome following an acute coronary event. Meticulous insulin-based metabolic care and a proper use of existing evidence-based treatment and when suited, early revascularisation, will improve the prognosis. It can be assumed that improved awareness of the glucometabolic condition among patients with acute coronary events may open for new secondary preventive treatment strategies in this patient category

Admission Glucose Levels and Associated Risk for Heart Failure After Myocardial Infarction in Patients Without Diabetes.

Background Dysglycemia at acute myocardial infarction (AMI) is common and is associated with mortality. Information on other outcomes is less well explored in patients without diabetes in a long-term perspective. We aimed to explore the relationship between admission glucose level and long-term outcomes in patients with AMI without diabetes in a nationwide setting. Methods and Results Patients without diabetes (n=45 468) with AMI registered in SWEDEHEART (Swedish Web-System for Enhancement and Development of Evidence-Based Care in Heart Disease Evaluated According to Recommended Therapies) and admission glucose ≤11 mmol/L (≤198 mg/dL) were followed for outcomes (AMI, heart failure, stroke, renal failure, and death) between 2012 and 2017 (mean follow-up time 3.3±1.7 years). The association between categorized glucose levels and outcomes was assessed in adjusted Cox proportional hazards regression analyses (glucose levels 4.0-6.0 mmol/L [72-109 mg/dL] as reference). Further nonfatal complications and their associated mortality were explored (patients without events served as a reference). A glucose level of 7.8-11.0 mmol/L (140-198 mg/dL) was associated with hospitalization for heart failure (hazard ratio [HR] 1.40 [95% CI, 1.30-1.51], P&lt;0.001), renal failure (1.17; 1.04-1.33, P=0.009), and death (1.31; 1.20-1.43, P&lt;0.001), but not with recurrent myocardial infarction (0.99; 0.92-1.07, P=0.849) or stroke (1.03; 0.88-1.19, P=0.742). Renal failure had the strongest association with future mortality (age-adjusted HR 4.93 [95% CI, 4.34-5.60], P&lt;0.001), followed by heart failure (3.71; 3.41-4.04, P&lt;0.001), stroke (3.39; 2.94-3.91, P&lt;0.001), and myocardial infarction (2.08; 1.88-2.30, P&lt;0.001). Conclusions Elevated glucose levels at AMI admission identifies patients without diabetes at increased risk of long-term complications: in particular, hospitalization for heart and renal failure. These results emphasize that glucose levels at admission could be useful in risk assessment after myocardial infarction