Impact of the SGLT2-inhibitor empagliflozin on inflammatory biomarkers after acute myocardial infarction - a post-hoc analysis of the EMMY trial.

BACKGROUND: SGTL2-inhibitors are a cornerstone in the treatment of heart failure, but data on patients with acute myocardial infarction (AMI) is limited. The EMMY trial was the first to show a significant reduction in NTproBNP levels as well as improved cardiac structure and function in post-AMI patients treated with Empagliflozin compared to placebo. However, data on the potential impact of SGLT2-inhibitors on inflammatory biomarkers after AMI are scarce. MATERIALS AND METHODS: The EMMY trial is an investigator-initiated, multicentre, double-blind, placebo-controlled trial, which enrolled patients after AMI, receiving either 10 mg Empagliflozin once daily or placebo over a period of 26 weeks on top of standard guideline-recommended therapy starting within 72 h after percutaneous coronary intervention. In this post-hoc subgroup analysis of the EMMY trial, we investigated inflammatory biomarkers of 374 patients. The endpoints investigated were the mean change in inflammatory biomarkers such as high-sensitive c-reactive protein (hsCRP), interleukin-6 (IL-6), neutrophils, leukocytes, neutrophile/lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) from baseline to 26 weeks. RESULTS: Baseline median (interquartile ranges) IL-6 was 17.9 pg/mL (9.0-38.7), hsCRP 18.9 mg/L (11.2-37.1), neutrophil count 7.9 x G/L (6.2-10.1), leukocyte count 10.8 x G/L (9.1-12.8) and neutrophile/lymphocyte ratio (NLR) of 0.74 (0.67-0.80). At week 26, a significant mean reduction in inflammatory biomarkers was observed, being 35.1 ± 3.2% (p < 0.001) for IL-6, 57.4 ± 0.7% (p < 0.001) for hsCRP, 26.1 ± 0.7% (p < 0.001) for neutrophils, 20.5 ± 0.6% (p < 0.001) for leukocytes, 10.22 ± 0.50% (p < 0.001) for NLR, and - 2.53 ± 0.92% for PLR (p = 0.006) with no significant difference between Empagliflozin and placebo treatment. CONCLUSION: Trajectories of inflammatory biomarkers showed a pronounced decline after AMI, but Empagliflozin treatment did not impact this decline indicating no central role in blunted systemic inflammation mediating beneficial effects.

Identification of contagious SARS-CoV-2 infected individuals by Roche's Rapid Antigen Test.

OBJECTIVES: Rapid antigen tests (RAT) can provide valuable information on the presence or absence SARS-CoV-2 within 15 min without the need of a laboratory. The analytical and diagnostic characteristics of available RATs has led to the question whether they can safely distinguish between infectious and non-infectious patients in an acute care setting. METHODS: Three nasopharyngeal swabs for the analysis by RAT, reverse transcriptase real time polymerase chain reaction (RT-qPCR), and a cell culture based infection assay were collected from 67 patients that presented to the emergency department of the University Hospital of Graz (Austria). The first swab was used for on-site RAT testing in the emergency department using the Roche SARS-CoV-2 RAT. The second swab was sent to the central laboratory of the hospital for RT-qPCR with two independent methods (Cepheid Xpert® Xpress SARS-CoV-2 assay and Roche Cobas SARS-CoV-2 Test) and repeat RAT testing using the same commercial test. With the third swab a cell culture-based infection assay was performed. RESULTS: The RATs performed from independent samples showed substantial agreement (Cohen's-kappa: 0.73, p<0.001). All patients with a positive RAT had positive RT-qPCR with cycle threshold (ct) values <25. Fifteen out of 55 RAT-negative samples were RT-qPCR positive with ct values between 25 and 40. The inoculation of cell cultures with RT-qPCR negative swabs and RT-qPCR positive swabs with ct values >25 did not induce cytopathic effects that were related to SARS-CoV-2. The infection assays from four RAT-negative patients showed cytopathic effects that were induced by other pathogens. CONCLUSIONS: The SARS-CoV-2 RAT from Roche Diagnostics is a valuable tool for managing symptomatic patients. RAT-negative patients may be regarded as non-contagious.

ENDOTHELIN-1 AS A RISK FACTOR IN RETINAL VEIN OCCLUSION.

PURPOSE: Retinal vein occlusion (RVO) risk factors largely coincide with cardiovascular risk factors. Endothelin-1 (ET-1), the most potent vasoconstrictor with proinflammatory properties, is a known cardiovascular risk factor. In this study, we explore the role of serum ET-1 as a potential risk factor for RVO. METHODS: Endothelin-1 serum levels were measured in patients with RVO and control subjects. Samples were measured using the sandwich enzyme-linked immunosorbent assay for the quantitative determination of human big endothelin-1 (Biomedica Group, Austria). RESULTS: The study consisted of 147 RVO patients and 150 control subjects. Median serum ET-1 was significantly higher in RVO patients (0.26 pmol/L; range, 0.19-0.37 pmol/L) compared with control subjects (0.10 pmol/L; range, 0.05-0.22 pmol/L) (P < 0.0001) independent of the occlusion site. The difference remained significant after adjusting for arterial hypertension, diabetes mellitus, history of stroke, history of myocardial infarction, history of venous thromboembolism, glomerular filtration rate, and c-reactive protein. CONCLUSION: In conclusion, our results suggest that ET-1 is a potential risk factor for all types of RVO.

Increased Kynurenine Indicates a Fatal Course of COVID-19.

(1) Background: An inefficient immune response accompanied by an overwhelming inflammatory reaction is involved in severe courses of COVID-19. Kynurenine (KYN) has important immune-modulatory functions and may contribute to a failure in controlling SARS-CoV-2. The present study aims to explore biomarkers that hint at a fatal outcome of COVID-19 early on. (2) Methods: We established a cohort of 148 hospitalized COVID-19 patients for this study. Thirty-one patients died due to a severe COVID-19 course, and 117 recovered within 90 days. We built a biobank by collecting left-over material from these patients whenever blood arrived at the central laboratory of our University hospital for analysis of routine markers. The scientific laboratory analysis comprised KYN, Tryptophan (TRP), KYN/TRP ratio, ferritin, interleukin-6 (IL-6), C-reactive protein (CRP), creatinine, N-terminal pro-natriuretic peptide (NTproBNP), troponin T (TnT), fibrinogen, D-Dimer, prothrombin time (PT), activated partial thromboplastin time (aPTT), antithrombin (AT), protein C, protein S, factor XIII, lupus aPTT, angiotensin-2, vitamin D metabolites, and telomeres in all COVID-19 patients. Basic clinical characteristics and anteceding diseases including cardiovascular, oncologic, renal, hypertension, pulmonary, metabolic (diabetes, obesity) were recorded in a database together with the laboratory data. (3) Results: At the time of diagnosis of SARS-CoV-2 infection those patients who deceased within 90 days afterwards due to COVID-19, had a significantly higher age, higher KYN, KYN/TRP ratio, ferritin, creatinine, and NTproBNP values than SARS-CoV-2 patients who survived COVID-19 along the same time span. In a Kaplan-Meier analysis the variables age, KYN, ferritin, D-Dimer, TnT, NTproBNP, and creatinine showed a significant influence on survival time. Gender, however, showed no influence. In a combined Cox regression analysis KYN had the highest hazard ratio (1.188, 95% CI: 1.071-1.319) followed by age (1.041, 95% CI: 1.011-1.073). In a ROC analysis, KYN values above the cut off limit of 4.82 nmol/l (as specified by Youden index) had a sensitivity of 82% (95% CI: 66-95%) and a specificity of 72% (95% CI: 65-82%) to predict COVID-19 related death within 90 days observation time. (4) Conclusions: Kynurenine is a promising blood biomarker to predict an increased risk of mortality in SARS-CoV-2 infected people already at the time of the first positive SARS-CoV-2 verification detected in these persons.

Hypothyroidism Exacerbates Thrombophilia in Female Rats Fed with a High Fat Diet.

Clotting abnormalities are discussed both in the context with thyroid dysfunctions and obesity caused by a high fat diet. This study aimed to investigate the impact of hypo-, or hyperthyroidism on the endogenous thrombin potential (ETP), a master indicator of clotting activation, on Sprague Dawley rats fed a normal or high fat diet. Female Sprague Dawley rats (n = 66) were grouped into normal diet (ND; n = 30) and high-fat diet (HFD; n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment ETP, body weight and food intake were analyzed. Successfully induced thyroid dysfunction was shown by T3 levels, both under normal and high fat diet. Thyroid dysfunction was accompanied by changes in calorie intake and body weight. In detail, compared to euthyroid controls, hypothyroid rats showed significantly increased-and hyperthyroid animals significantly decreased-ETP levels. High fat diet potentiated these effects in both directions. In summary, we are the first to show that hypothyroidism and high fat diet potentiate the thrombotic capacity of the clotting system in Sprague Dawley rats. This effect may be relevant for cardiovascular disease where thyroid function is poorly understood as a pathological contributor in the context of clotting activity and obesogenic nutrition.

Oxidized LDL Is Strictly Limited to Hyperthyroidism Irrespective of Fat Feeding in Female Sprague Dawley Rats.

Metabolic dysfunctions might play a crucial role in the pathophysiology of thyroid dysfunctions. This study aimed to investigate the impact of a controlled diet (normal versus high fat feeding) on hypothyroid and hyperthyroid Sprague Dawley rats. Female Sprague Dawley rats (n = 66) were grouped into normal diet (n = 30) and high-fat diet (n = 36) groups and subdivided into controls, hypothyroid and hyperthyroid groups, induced through propylthiouracil or triiodothyronine (T3) treatment, respectively. After 12 weeks of treatment metabolic parameters, such as oxidized LDL (oxLDL), malondialdehyde (MDA), 4-hydroxynonenal (HNE), the lipid profile, body weight and food intake parameters were analyzed. Successfully induced thyroid dysfunctions were shown by T3 levels, both under normal and high fat diet. Thyroid dysfunctions were accompanied by changes in calorie intake and body weight as well as in the lipid profile. In detail, hypothyroid rats showed significantly decreased oxLDL levels, whereas hyperthyroid rats showed significantly increased oxLDL levels. These effects were seen under high fat diet and were less pronounced with normal feeding. Taken together, we showed for the first time in female SD rats that only hyper-, but not hypothyroidism, is associated with high atherogenic oxidized LDL irrespective of normal or high-fat diet in Sprague Dawley rats.

GLP-2 and leptin are associated with hyperinsulinemia in non-obese female migraineurs.

OBJECTIVE: Impaired insulin metabolism has been implicated in migraine. However, to date only some putative effects, especially regarding the involvement of adipocytokines and glucagon-like peptides (GLPs), have been described. The aim of the present study was to investigate adipocytokines and GLPs in non-obese female migraineurs. METHODS: Various parameters of the insulin metabolism and body measurements were determined in 84 non-obese female subjects. RESULTS: We found highly significantly increased insulin levels with an odds ratio of 10.62 for migraine. Leptin and GLP-2 levels were also increased and correlated with insulin. Logistic regression analysis of leptin and GLP-2 revealed odds ratios of 3.79 and 4.26 for migraine, respectively, when comparing the lowest with the highest quartile of the test variable in the complete study cohort. DISCUSSION: We show that non-obese female migraineurs suffer from hyperinsulinemia, which is associated with elevated leptin and GLP-2 levels. Increased leptin and GLP-2 are risk factors for migraine. Our data suggest that migraine is associated with a higher risk for insulin resistance and its clinical consequences.

Increased dopamine is associated with the cGMP and homocysteine pathway in female migraineurs.

BACKGROUND: The group of catecholamines, which include dopamine, adrenaline, and noradrenaline, are neurotransmitters which have been considered to play a role in the pathogenesis of migraine. However, the impact of catecholamines, especially dopamine on migraine as well as the exact mechanisms is not clear to date as previous studies have yielded in part conflicting results. OBJECTIVE: This study aimed to produce a comprehensive examination of dopamine in migraineurs. METHODS: Catecholamines and various parameters of the homocysteine, folate, and iron metabolism as well as cyclic guanosine monophosphate (cGMP) and inflammatory markers were determined in 135 subjects. RESULTS: We found increased dopamine levels in the headache free period in female migraineurs but not in male patients. Increased dopamine is associated with a 3.30-fold higher risk for migraine in women. We found no significant effects of aura symptoms or menstrual cycle phases on dopamine levels. Dopamine is strongly correlated with cGMP and the homocysteine-folate pathway. CONCLUSION: We show here that female migraineurs exhibit increased dopamine levels in the headache free period which are associated with a higher risk for migraine.

Human cytomegalovirus load in various body fluids of congenitally infected newborns.

BACKGROUND: Congenital human cytomegalovirus (hCMV) infection is the most common intrauterine viral disease in western countries. Little is known about hCMV virus load in various body fluids of congenitally infected children. OBJECTIVES: To determine virus load in various body fluids. To assess the impact of hCMV virus load to predict the outcome of congenitally infected newborns and efficacy of antiviral therapy. STUDY DESIGN: Cord vein blood, urine, and cerebrospinal fluid (CSF) of congenitally hCMV-infected children were investigated and hCMV load was determined by quantitative polymerase chain reaction (PCR). Fourteen of 30 children had clinical symptoms and/or pathological laboratory results and 16 had none of them at birth. Ganciclovir was given to 21 children (10 of them with symptoms, 11 of them without symptoms). Viral load before and after therapy was measured. RESULTS: There was a significant difference between median virus load in cord vein blood (2.3 x 10(3) copies per ml) and in urine (4.2 x 10(5) copies per ml; P<0.001) at diagnosis of congenital hCMV infection. At that time, no significant difference of virus load was found between the various groups (symptomatic vs. asymptomatic; with therapy vs. without therapy), neither in serum nor in urine. Comparing median virus load in urine before (3.0 x 10(5) copies per ml) and after therapy (2.0 x 10(3) copies per ml), a significant decrease was observed (P<0.001). Virus load in CSF was always found to be less than 400 copies per ml, and only those children with symptoms showed a positive result. CONCLUSION: At birth, virus load in urine seems to be superior to that in cord vein blood to reflect the situation in the organs precisely. As predicting factor for the risk of developing symptoms, only hCMV detection in the CSF appears to be promising. The significant decrease of virus load in children with therapy may reflect the efficacy of therapy. Studies including a greater number of children are needed.

Expression of adhesion molecules in allergic lung diseases.

Endothelial adherence and migration of leukocytes into tissue is mediated by different sets of adhesion molecules. The expression of these sets might not only preselect the types of leukocytes that enter the inflammatory sites, but also activate these leukocytes, induce adherence to epithelial cells, and cause the release of cytokines. Atopic asthma, extrinsic allergic alveolitis, and sarcoidosis as examples of immunologic lung diseases were investigated for the expression of adhesion molecules. Bronchial biopsies in chronic obstructive lung disease (COPD) and resected lung tissue of juvenile emphysema were chosen for controls. Immunohistochemistry was done on sections from bronchial and transbronchial biopsies and on smears from bronchoalveolar lavage cells. In all three types of immune disorders, lymphocytes expressed the integrins alpha4/beta1 (VLA4) and ICAM3, whereas lymphocytes in COPD bronchitis and in emphysema controls were unreactive. Eosinophils in atopic asthma bronchitis in contrast to COPD bronchitis also expressed both VLA4 and ICAM3. The expression of VCAM1 on endothelial cells was only seen in atopic asthma and was related to disease activity. The expression of other adhesion molecules was nonspecific. Expression of VCAM1 on endothelial cells and its ligand VLA4 on lymphocytes and eosinophils seems to be a specific event in atopic asthma. Expression of VLA4 and ICAM3 on lymphocytes, however, might be a specific event in all three immune reactions.