Plasminogen activator inhibitor 1 (PAI-1) is the main regulator of endogenous fibrinolysis, overriding the impact of other constituents of fibrinolysis. In plasma, it can be found in three forms: ...active, latent and inactive. There are numerous commercially available tests, analysing the activity of PAI-1 or the antigen level, with variable correlations between the two. PAI-1 has been extensively studied regarding incidence and outcomes of acute coronary syndromes, and showed positive association with both in numerous studies. Higher PAI-1 has been associated with worse short- and long-term outcomes. Studies are more consistent in the primary percutaneous coronary intervention era. Higher rise of PAI-1 within the first 24 h of acute myocardial infarction has been linked to some of its high-risk features. The circadian pattern of PAI-1 kinetics has been previously described, and the mechanisms behind this phenomenon and its impact on the incidence of acute coronary syndromes are well known. Further investigations are needed to test the safety and efficacy of PAI-1 as a pharmacological target in cardiovascular diseases.
•PAI-1 analysis is complex, with various tests, equivocal correlations•Related to incidence, worse outcome of acute coronary syndromes•Related to high-risk features of myocardial infarction•Responsible for circadian pattern of myocardial infarction symptom onset
This prospective observational study evaluated the possible mechanisms of action of SGLT2 inhibitors (SGLT2i) in patients with type 2 diabetes mellitus (T2DM) without overt heart disease.
The study ...was designed to verify whether SGLT2i impact biomarkers of: myocardial stress–NT-proBNP, inflammation–high sensitivity C-reactive protein, oxidative stress –myeloperoxidase, functional and structural echocardiographic parameters, in patients with T2DM on metformin (heart failure stages A and B) who needed treatment intensification with a second antidiabetic agent. The patients were divided in two groups – the ones planned to receive SGLT2i or DPP-4 inhibitor (except saxagliptin). At baseline, and after six months of therapy, 64 patients underwent blood analysis, physical and echocardiography examination.
There were no significant differences between the two groups in terms of biomarkers of myocyte and oxidative stress, inflammation and blood pressure. Body mass index, triglycerides, aspartate aminotransferase, uric acid, E/E′, deceleration time and systolic pressure in the pulmonary artery significantly decreased, while stroke volume, indexed stroke volume, high-density lipoprotein, hematocrit and hemoglobin significantly increased in the group on SGLT2i.
According to the results, SGLT2i mechanisms of action comprise rapid changes in body composition and metabolic parameters, reduced cardiac load and improvement in diastolic and systolic parameters.
•SGLT2 inhibitors reduce the risk of major cardiovascular events.•SGLT2 inhibitors are efficient in primary/secondary prevention of heart failure.•They show pleiotropic effects in patients at risk of developing heart failure.•These effects are: rapid changes in body composition and metabolic parameters.•Furthermore, they reduce cardiac load, improve diastolic and systolic function.
The aim of our study was to perform verification of serum indices on three clinical chemistry platforms.
This study was done on three analyzers: Abbott Architect c8000, Beckman Coulter AU5800 (BC) ...and Roche Cobas 6000 c501. The following analytical specifications were verified: precision (two patient samples), accuracy (sample with the highest concentration of interferent was serially diluted and measured values compared to theoretical values), comparability (120 patients samples) and cross reactivity (samples with increasing concentrations of interferent were divided in two aliquots and remaining interferents were added in each aliquot. Measurements were done before and after adding interferents).
Best results for precision were obtained for the H index (0.72%-2.08%). Accuracy for the H index was acceptable for Cobas and BC, while on Architect, deviations in the high concentration range were observed (y=0.02 0.01-0.07+1.07 1.06-1.08x). All three analyzers showed acceptable results in evaluating accuracy of L index and unacceptable results for I index. The H index was comparable between BC and both, Architect (Cohen's κ 95% CI=0.795 0.692-0.898) and Roche (Cohen's κ 95% CI=0.825 0.729-0.922), while Roche and Architect were not comparable. The I index was not comparable between all analyzer combinations, while the L index was only comparable between Abbott and BC. Cross reactivity analysis mostly showed that serum indices measurement is affected when a combination of interferences is present.
There is heterogeneity between analyzers in the hemolysis, icteria, lipemia (HIL) quality performance. Verification of serum indices in routine work is necessary to establish analytical specifications.
The aim of the study was to perform analytical verification and comparison of chromogenic assays for determination of dabigatran, rivaroxaban and apixaban concentration on BCSXP and STA Compact Max ...analysers.
Precision, linearity, measurement uncertainty estimation and determination of limit of blank, limit of determination and limit of quantification were calculated. Analytical performance specifications were set according to manufacturer specifications and literature data on between laboratory variability. Comparison of the methods was done using Bland-Altman and Passing-Bablok regression analysis.
Obtained results have shown acceptable precision on STA Compact Max only for dabigatran (CV = 3.5%) at lower concentration level comparing to manufacturer declaration (CV = 3.6%). On BCSXP, the highest coefficient of variation has been shown for apixaban (6.1%) at lower concentration level. Within laboratory precision was not met on STA Compact Max for all assays. Bland-Altman analysis has shown statistically significant bias for dabigatran (23.2%, 95%CI 11.2 - 35.3; P < 0.001) and apixaban (8.4%, 95%CI 1.2 - 15.6; P = 0.023). Passing-Bablok regression analysis has shown systematic and proportional deviation between methods for rivaroxaban (y = 6.52 (2.94 to 11.83) + 0.84 (0.80 to 0.89) x.
Chromogenic assays for dabigatran, rivaroxaban and apixaban on BCSXP and STA Compact Max analysers are shown as methods with satisfactory long-term analytical performance specifications for determination of direct oral anticoagulants in clinical laboratories. However, we cannot recommend interchangeable use because of the significant bias between assays.
Paraoxonase 1 (PON1) is the enzyme that removes carcinogenic radicals from lipids. The aim of the study was to investigate the differences in PON1 activity and oxidation stress parameters between ...patients with cervical intraepithelial neoplasia (CIN) and healthy controls.
The study included 65 women with CIN and 109 healthy women. Lipid parameters were determined on Cobas Integra 400 plus (Roche, Mannheim, Germany). Tiols and reduced glutathione (GSH) were determined spectrophotometric using Eliman reagent. Activity of PON1 was assessed with two substrates, paraoxon and phenylacetate by spectrophotometric method. Malondialdehyde (MDA) was determined by high performance liquid chromatography (Shimadzu Corporation, Kyoto, Japan). Mann-Whitney-test, t-test, χ2-test, correlation and logistic regression was used in statistical analysis. P < 0.05 was considered statistically significant.
The basal (P = 0.929) and NaCl-stimulated (P = 0.985) PON1 activity and activities standardised on the concentration of high-density lipoprotein (HDL; P = 0.076; P = 0.065, respectively) and apolipoprotein AI (apo AI; P = 0.444; P = 0.499, respectively) as well as PON1 phenotypes (P = 0.842) did not differ significantly between the groups. The PON1 arylesterase activity (53±19 kU/L vs. 77±17 kU/L; P < 0.001) and HDL-standardized activity (37 (28-44) kU/mmol
. 43 (37-50) kU/mmol; P < 0.001) and apoAI (29±11 kU/g
. 44±11 kU/g; P < 0.001) was significantly reduced in the CIN group. The concentration of the thiol groups was similar (P = 0.519), of MDA was lower (0.39 (0.27-0.55) µmol/L
. 0.76 (0.57-1.15) µmol/L; P < 0.001) and of GSH was higher (112.0 (66.0-129.6) µg/mL
. 53.4 (34.8-134.4) µg/mL; P < 0.001) in the CIN group.
Reduced PON1 arylesterase activity, lower MDA and higher GSH concentration were observed in CIN patients.
Three major cardiovascular outcome trials (CVOTs) with a new class of antidiabetic drugs - sodium-glucose cotransporter 2 (SGLT2) inhibitors (EMPA-REG OUTCOME trial with empagliflozin, CANVAS Program ...with canagliflozin, DECLARE-TIMI 58 with dapagliflozin) unexpectedly showed that cardiovascular outcomes could be improved possibly due to a reduction in heart failure risk, which seems to be the most sensitive outcome of SGLT2 inhibition. No other CVOT to date has shown any significant benefit on heart failure events. Even more impressive findings came recently from the DAPA-HF trial in patients with confirmed and well-treated heart failure: Dapagliflozin was shown to reduce heart failure risk for patients with heart failure with reduced ejection fraction regardless of diabetes status. Nevertheless, despite their possible wide clinical implications, there is much doubt about the mechanisms of action and a lot of questions to unravel, especially now when their benefits translated to non-diabetic patients, rising doubts about the validity of some current mechanistic assumptions.The time frame of their cardiovascular benefits excludes glucose-lowering and antiatherosclerotic-mediated effects and multiple other mechanisms, direct cardiac as well as systemic, are suggested to explain their early cardiorenal benefits. These are: Anti-inflammatory, antifibrotic, antioxidative, antiapoptotic properties, then renoprotective and hemodynamic effects, attenuation of glucotoxicity, reduction of uric acid levels and epicardial adipose tissue, modification of neurohumoral system and cardiac fuel energetics, sodium-hydrogen exchange inhibition. The most logic explanation seems that SGLT2 inhibitors timely target various mechanisms underpinning heart failure pathogenesis. All the proposed mechanisms of their action could interfere with evolution of heart failure and are discussed separately within the main text.
Clinical application of rivaroxaban and apixaban does not require therapeutic monitoring. Commercial anti-activated factor X (anti-FXa) inhibition methods for all anti-FXa drugs are based on the same ...principle, so there are attempts to evaluate potential clinical application of heparin-calibrated anti-FXa assay as an alternative method for direct FXa inhibitors. We aimed to evaluate relationship between anti-FXa methods calibrated with low molecular weight heparin (LMWH) and with drug specific calibrators, and to determine whether commercial LMWH anti-FXa assay can be used to exclude the presence of clinically relevant concentrations of rivaroxaban and apixaban.
Low molecular weight heparin calibrated reagent (Siemens Healthineers, Marburg, Germany) was used for anti-FXa activity measurement. Innovance heparin (Siemens Healthineers, Marburg, Germany) calibrated with rivaroxaban and apixaban calibrators (Hyphen BioMed, Neuville-sur-Oise, France) was used for quantitative determination of FXa inhibitors.
Analysis showed good agreement between LMWH calibrated and rivaroxaban calibrated activity (κ = 0.76) and very good agreement with apixaban calibrated anti-Xa activity (κ = 0.82), respectively. Low molecular weight heparin anti-FXa activity cut-off values of 0.05 IU/mL and 0.1 IU/mL are suitable for excluding the presence of clinically relevant concentrations (< 30 ng/mL) of rivaroxaban and apixaban, respectively. Concentrations above 300 ng/mL exceeded upper measurement range for LMWH anti-FXa assay and cannot be determined by this method.
Low molecular weight heparin anti-FXa assay can be used in emergency clinical conditions for ruling out the presence of clinically relevant concentrations of rivaroxaban and apixaban. However, use of LMWH anti-FXa assay is not appropriate for their quantitative determination as an interchangeable method.
To determine the relationship between plasminogen activator inhibitor-1 (PAI-1) activity rise during the first 24 hours of ST-elevation myocardial infarction (STEMI) treatment and death after 5 ...years.
From May 1, 2009 to March 23, 2010, 87 STEMI patients treated with primary percutaneous coronary intervention (PCI) at the Sestre Milosrdnice University Hospital Center were consecutively enrolled in prospective single-center cohort study. PAI-1 activity was determined on admission and 24 hours later. The primary end-point was death after 5 years. The predictive value of PAI-1 activity variables as biomarkers of death was assessed using receiver operating characteristic (ROC) curve, independent predictors of death were assessed using multivariate Cox regression, and covariates independently related to higher PAI-1 activity rise were assessed using linear regression.
Two patients died during the hospital treatment and 11 during the follow-up. PAI-1 activity rise had the largest area under curve (0.748) for predicting death rate (optimal cut-off point 3.7 U/mL, sensitivity 53.8%, specificity 90.5%). Patients with PAI-1 activity rise higher than 3.7 U/mL had significantly higher mortality (P<0.001). Kaplan-Meier survival curve diverged within the first year after STEMI. Independent predictors of death were PAI-1 rise and final Thrombolysis in Myocardial Infarction flow. PAI-1 activity rise was independently related to heart failure, thrombus aspiration, and body weight.
PAI-1 activity rise higher than 3.7 U/mL is associated with higher 5-year death rate in STEMI patients treated with primary PCI.
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