Publications

In patients with type 2 diabetes mellitus (T2DM) an association between severe hypoglycaemic episodes and the risk of cardiovascular (CV) morbidity and mortality has been previously established.

Multiple sclerosis (MS) is a central nervous system chronic neuroinflammatory disease followed by neurodegeneration. The diagnosis is based on clinical presentation, cerebrospinal fluid testing and magnetic resonance imagining. There is still a lack of a diagnostic blood-based biomarker for MS. Due to the cost and difficulty of diagnosis, new and more easily accessible methods are being sought. New biomarkers should also allow for early diagnosis. Additionally, the treatment of MS should lead to the personalization of the therapy. MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) as well as their target genes participate in pathophysiology processes in MS. Although the detailed mechanism of action of non-coding RNAs (ncRNAs, including miRNAs and lncRNAs) on neuroinflammation in MS has not been fully explained, several studies were conducted aiming to analyse their impact in MS. In this article, we review up-to-date knowledge on the latest research concerning the ncRNAs in MS and evaluate their role in neuroinflammation. We also point out the most promising ncRNAs which may be promising in MS as diagnostic and prognostic biomarkers.

Dual antiplatelet therapy (DAPT) prevents ischemic events in patients with acute coronary syndrome (ACS), but is associated with increased risk of bleeding events. Symmetric dimethylarginine (SDMA) is one of nitric oxide (NO)-related pathway metabolites and stands as a promising biomarker of early chronic kidney disease (CKD) and cardiovascular diseases (CVDs).

MicroRNAs (miRNAs) are small, non-coding RNAs, able to regulate cellular functions by induction of mRNA degradation and post-transcriptional repression of gene expression. Platelets are the major source of circulating miRNAs, with significant regulatory potential on cardiovascular pathophysiology and other diseases. MiRNAs have been shown to modify the expression of platelet proteins, which influence the platelets reactivity. Circulating miRNAs can be determined from plasma, serum, or whole blood, and they can be used as diagnostic and prognostic biomarkers as well as therapeutic targets including cardiovascular diseases (CVDs). Herein, we present original results from bioinformatic analyses, which identified top 22 platelet-related miRNAs including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p as widely involved in platelet reactivity and associated diseases, including CVDs, Alzheimer's and cerebrovascular diseases, cancer and hypertension. Analysis focused on the identification of the highly regulatory targets shared between those miRNAs identified 43 of them. Best ranked genes associated with overall platelet activity and most susceptible for noncoding regulation were PTEN, PIK3R1, CREB1, APP, and MAPK1. Top targets also strongly associated with CVDs were VEGFA, IGF1, ESR1, BDNF, and PPARG. Top targets associated with other platelet-related diseases including cancer identified in our study were TP53, KRAS, and CCND1. The most affected pathways by top miRNAs and top targets included diseases of signal transduction by Growth Factor Receptors (GDFRs) and second messengers, platelet activation, signaling, and aggregation, signaling by VEGF, MAPK family signaling cascades, and signaling by Interleukins. Terms specific only for platelet-related miRNAs included coronary artery disease, platelet degranulation, and neutrophil degranulation, while for the top platelet-related genes it was Estrogen Signaling Receptor (ESR) mediated signaling, extra-nuclear estrogen signaling, and endometriosis. Our results show the novel features of platelet physiology and may provide a basis for further clinical studies focused on platelet reactivity. They also show in which aspects miRNAs can be promising biomarkers of platelet-related pathological processes.

Despite the positive effects of endurance training on the cardiovascular (CV) system, excessive exercise induces not only physiological adaptations but also adverse changes in CV system, including the heart. We aimed to evaluate the selected miRNAs expression based on bioinformatic analysis and their changes before and after an ultramarathon run.

The vascular system is largely exposed to the effect of changing flow conditions. Vascular cells can sense flow and its changes. Flow sensing is of pivotal importance for vascular remodeling. In fact, it influences the development and progression of atherosclerosis, controls its location and has a major influx on the development of local complications. Despite its importance, the research community has traditionally paid scarce attention to studying the association between different flow conditions and vascular biology. More recently, a growing body of evidence has been accumulating, revealing that ncRNAs play a key role in the modulation of several biological processes linking flow-sensing to vascular pathophysiology. This review summarizes the most relevant evidence on ncRNAs that are directly or indirectly responsive to flow conditions to the benefit of the clinician, with a focus on the underpinning mechanisms and their potential application as disease biomarkers.

High on-treatment platelet reactivity (HTPR) remains a major problem in the acute management of ST-elevation myocardial infarction (STEMI), leading to higher rates of stent thrombosis and mortality. We aimed to investigate a novel, prehospital treatment strategy using cangrelor and tested its pharmacodynamic effects in a model using healthy volunteers.

Coronavirus disease 2019 (COVID-19) is associated with a hypercoagulable state. It has been hypothesized that higher-dose anticoagulation, including therapeutic-dose and intermediate-dose anticoagulation, is superior to prophylactic-dose anticoagulation in the treatment of COVID-19. This meta-analysis evaluated the efficacy and safety of higher-dose anticoagulation compared with prophylactic-dose anticoagulation in patients with COVID-19. Ten randomized controlled open-label trials with a total of 5,753 patients were included. The risk of death and net adverse clinical events (including death, thromboembolic events, and major bleeding) were similar between higher-dose and prophylactic-dose anticoagulation (risk ratio (RR) 0.96, 95% CI, 0.79-1.16, P = 0.66 and RR 0.87, 95% CI, 0.73-1.03, P = 0.11, respectively). Higher-dose anticoagulation, compared with prophylactic-dose anticoagulation, decreased the risk of thromboembolic events (RR 0.63, 95% CI, 0.47-0.84, P = 0.002) but increased the risk of major bleeding (RR 1.76, 95% CI, 1.19-2.62, P = 0.005). The risk of death showed no statistically significant difference between higher-dose anticoagulation and prophylactic-dose anticoagulation in noncritically ill patients (RR 0.87, 95% CI, 0.50-1.52, P = 0.62) and in critically ill patients with COVID-19 (RR 1.04, 95% CI, 0.93-1.17, P = 0.5). The risk of death was similar between therapeutic-dose vs. prophylactic-dose anticoagulation (RR 0.92, 95% CI 0.69-1.21, P = 0.54) and between intermediate-dose vs. prophylactic-dose anticoagulation (RR 1.01, 95% CI 0.63-1.61, P = 0.98). In patients with markedly increased d-dimer levels, higher-dose anticoagulation was also not associated with a decreased risk of death as compared with prophylactic-dose anticoagulation (RR 0.86, 95% CI, 0.64-1.16, P = 0.34). Without any clear evidence of survival benefit, these findings do not support the routine use of therapeutic-dose or intermediate-dose anticoagulation in critically or noncritically ill patients with COVID-19.

Convalescent plasma is a suggested treatment for Coronavirus disease 2019 (Covid-19), but its efficacy is uncertain. We aimed to evaluate whether the use of convalescent plasma is associated with improved clinical outcomes in patients with Covid-19.In this systematic review and meta-analysis, we searched randomized controlled trials investigating the use of convalescent plasma in patients with Covid-19 in Medline, Embase, Web of Science, Cochrane Library, and medRxiv from inception to October 17, 2021. Two reviewers independently extracted the data. The primary efficacy outcome was all-cause mortality. The Cochrane Risk of Bias Tool and GRADE (Grading of Recommendations Assessment, Development and Evaluation) method were used. This study was registered with PROSPERO, CRD42021284861. Of the 8874 studies identified in the initial search, sixteen trials comprising 16 317 patients with Covid-19 were included. In the overall population, the all-cause mortality was 23.8% (2025 of 8524) with convalescent plasma and 24.4% (1903 of 7769) with standard of care (risk ratio (RR) 0.97, 95% CI 0.90-1.04) (high-certainty evidence). All-cause mortality did not differ in the subgroups of noncritically ill (21.7% [1288 of 5929] vs. 22.4% [1320 of 5882]) and critically ill (36.9% [518 of 1404] vs. 36.4% [455 of 1247]) patients with Covid-19. The use of convalescent plasma in patients who tested negative for anti-SARS-CoV-2 antibodies at baseline was not associated with significantly improved survival (RR 0.94, 95% CI 0.87-1.02). In the overall study population, initiation of mechanical ventilation (RR 0.97, 95% CI 0.88-1.07), time to clinical improvement (HR 1.09, 95% CI 0.91-1.30), and time to discharge (HR 0.95, 95% CI 0.89-1.02) were similar between the two groups. In patients with Covid-19, treatment with convalescent plasma, as compared with control, was not associated with lower all-cause mortality or improved disease progression, irrespective of disease severity and baseline antibody status.

MicroRNAs (miRNAs) are small, non-coding RNAs, able to regulate cellular functions by induction of mRNA degradation and post-transcriptional repression of gene expression. Platelets are the major source of circulating miRNAs, with significant regulatory potential on cardiovascular pathophysiology and other diseases. MiRNAs have been shown to modify the expression of platelet proteins, which influence the platelets reactivity. Circulating miRNAs can be determined from plasma, serum, or whole blood, and they can be used as diagnostic and prognostic biomarkers as well as therapeutic targets including cardiovascular diseases (CVDs). Herein, we present original results from bioinformatic analyses, which identified top 22 platelet-related miRNAs including hsa-miR-320a, hsa-miR-16-5p, hsa-miR-106a-5p, hsa-miR-320b, hsa-miR-15a-5p, hsa-miR-15b-5p, hsa-miR-195-5p, hsa-miR-92a-3p as widely involved in platelet reactivity and associated diseases, including CVDs, Alzheimer's and cerebrovascular diseases, cancer and hypertension. Analysis focused on the identification of the highly regulatory targets shared between those miRNAs identified 43 of them. Best ranked genes associated with overall platelet activity and most susceptible for noncoding regulation were PTEN, PIK3R1, CREB1, APP, and MAPK1. Top targets also strongly associated with CVDs were VEGFA, IGF1, ESR1, BDNF, and PPARG. Top targets associated with other platelet-related diseases including cancer identified in our study were TP53, KRAS, and CCND1. The most affected pathways by top miRNAs and top targets included diseases of signal transduction by Growth Factor Receptors (GDFRs) and second messengers, platelet activation, signaling, and aggregation, signaling by VEGF, MAPK family signaling cascades, and signaling by Interleukins. Terms specific only for platelet-related miRNAs included coronary artery disease, platelet degranulation, and neutrophil degranulation, while for the top platelet-related genes it was Estrogen Signaling Receptor (ESR) mediated signaling, extra-nuclear estrogen signaling, and endometriosis. Our results show the novel features of platelet physiology and may provide a basis for further clinical studies focused on platelet reactivity. They also show in which aspects miRNAs can be promising biomarkers of platelet-related pathological processes.

This study evaluated and compared the performance of simplified acute physiology score 3 (SAPS 3) for predicting in-hospital mortality in COVID-19 patients admitted to intensive care units (ICUs) with and without diabetes in Austria. The Austrian national public health institute (GÖG) data of COVID-19 patients admitted to ICUs (n = 5850) were analyzed. Three versions of SAPS 3 were used: standard equation, Central European equation, and Austrian equation customized for COVID-19 patients. The observed in-hospital mortality was 38.9%, 42.9%, and 37.3% in all, diabetes, and non-diabetes patients, respectively. The overall C-statistics was 0.69 with an insignificant (p = 0.193) difference between diabetes (0.70) and non-diabetes (0.68) patients. The Brier score was > 0.20 for all SAPS 3 equations in all cohorts. Calibration was unsatisfactory for both standard and Central European equations in all cohorts, whereas it was satisfactory for the Austrian equation in diabetes patients only. The SAPS 3 score demonstrated low discrimination and accuracy in Austrian COVID-19 patients, with an insignificant difference between diabetes and non-diabetes. All equations were miscalibrated particularly in non-diabetes patients, while the Austrian equation showed satisfactory calibration in diabetes patients only. Both uncalibrated and calibrated versions of SAPS 3 should be used with caution in COVID-19 patients.

In patients with type 2 diabetes mellitus (T2DM) an association between severe hypoglycaemic episodes and the risk of cardiovascular (CV) morbidity and mortality has been previously established.

In patients with type 2 diabetes mellitus (T2DM) an association between severe hypoglycaemic episodes and the risk of cardiovascular (CV) morbidity and mortality has been previously established.

SARS-CoV-2 tropism for the ACE2 receptor, along with the multifaceted inflammatory reaction, is likely to drive the generalized hypercoagulable and thrombotic state seen in patients with COVID-19. Using the original bioinformatic workflow and network medicine approaches we reanalysed four coronavirus-related expression datasets and performed co-expression analysis focused on thrombosis and ACE2 related genes. We identified microRNAs (miRNAs) which play role in ACE2-related thrombosis in coronavirus infection and further, we validated the expressions of precisely selected miRNAs-related to thrombosis (miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p) in 79 hospitalized COVID-19 patients and 32 healthy volunteers by qRT-PCR. Consequently, we aimed to unravel whether bioinformatic prioritization could guide selection of miRNAs with a potential of diagnostic and prognostic biomarkers associated with disease severity in patients hospitalized for COVID-19. In bioinformatic analysis, we identified EGFR, HSP90AA1, APP, TP53, PTEN, UBC, FN1, ELAVL1 and CALM1 as regulatory genes which could play a pivotal role in COVID-19 related thrombosis. We also found miR-16-5p, miR-27a-3p, let-7b-5p and miR-155-5p as regulators in the coagulation and thrombosis process. predictions were further confirmed in patients hospitalized for COVID-19. The expression levels of miR-16-5p and let-7b in COVID-19 patients were lower at baseline, 7-days and 21-day after admission compared to the healthy controls (p < 0.0001 for all time points for both miRNAs). The expression levels of miR-27a-3p and miR-155-5p in COVID-19 patients were higher at day 21 compared to the healthy controls (p = 0.007 and p < 0.001, respectively). A low baseline miR-16-5p expression presents predictive utility in assessment of the hospital length of stay or death in follow-up as a composite endpoint (AUC:0.810, 95% CI, 0.71-0.91, p < 0.0001) and low baseline expression of miR-16-5p and diabetes mellitus are independent predictors of increased length of stay or death according to a multivariate analysis (OR: 9.417; 95% CI, 2.647-33.506; p = 0.0005 and OR: 6.257; 95% CI, 1.049-37.316; p = 0.044, respectively). This study enabled us to better characterize changes in gene expression and signalling pathways related to hypercoagulable and thrombotic conditions in COVID-19. In this study we identified and validated miRNAs which could serve as novel, thrombosis-related predictive biomarkers of the COVID-19 complications, and can be used for early stratification of patients and prediction of severity of infection development in an individual. ACE2, angiotensin-converting enzyme 2AF, atrial fibrillationAPP, Amyloid Beta Precursor ProteinaPTT, activated partial thromboplastin timeAUC, Area under the curveAβ, amyloid betaBMI, body mass indexCAD, coronary artery diseaseCALM1, Calmodulin 1 geneCaM, calmodulinCCND1, Cyclin D1CI, confidence intervalCOPD, chronic obstructive pulmonary diseaseCOVID-19, Coronavirus disease 2019CRP, C-reactive proteinCV, CardiovascularCVDs, cardiovascular diseasesDE, differentially expressedDM, diabetes mellitusEGFR, Epithelial growth factor receptorELAVL1, ELAV Like RNA Binding Protein 1FLNA, Filamin AFN1, Fibronectin 1GEO, Gene Expression OmnibushiPSC-CMs, Human induced pluripotent stem cell-derived cardiomyocytesHSP90AA1, Heat Shock Protein 90 Alpha Family Class A Member 1Hsp90α, heat shock protein 90αICU, intensive care unitIL, interleukinIQR, interquartile rangelncRNAs, long non-coding RNAsMI, myocardial infarctionMiRNA, MiR, microRNAmRNA, messenger RNAncRNA, non-coding RNANERI, network-medicine based integrative approachNF-kB, nuclear factor kappa-light-chain-enhancer of activated B cellsNPV, negative predictive valueNXF, nuclear export factorPBMCs, Peripheral blood mononuclear cellsPCT, procalcitoninPPI, Protein-protein interactionsPPV, positive predictive valuePTEN, phosphatase and tensin homologqPCR, quantitative polymerase chain reactionROC, receiver operating characteristicSARS-CoV-2, severe acute respiratory syndrome coronavirus 2SD, standard deviationTLR4, Toll-like receptor 4TM, thrombomodulinTP53, Tumour protein P53UBC, Ubiquitin CWBC, white blood cells.

Sodium-glucose co-transporter 2 inhibition reduces the risk of hospitalization for heart failure and for death in patients with symptomatic heart failure. However, trials investigating the effects of this drug class in patients following acute myocardial infarction are lacking.

Sodium-glucose cotransporter 2 (SGLT2), also known as solute carrier family 5 member 2 (SLC5A2), is a promising target for a new class of drugs primarily established as kidney-targeting, effective glucose-lowering agents used in diabetes mellitus (DM) patients. Increasing evidence indicates that besides renal effects, SGLT2 inhibitors (SGLT2i) have also a systemic impact via indirectly targeting the heart and other tissues. Our hypothesis states that the pleiotropic effects of SGLT2i are associated with their binding force, location of targets in the SGLT2 networks, targets involvement in signaling pathways, and their tissue-specific expression. Thus, to investigate differences in SGLT2i impact on human organisms, we re-created the SGLT2 interaction network incorporating its inhibitors and metformin and analyzed its tissue-specific expression using publicly available datasets. We analyzed it in the context of the so-called key terms ( autophagy, oxidative stress, aging, senescence, inflammation, AMPK pathways, and mTOR pathways) which seem to be crucial to elucidating the SGLT2 role in a variety of clinical manifestations. Analysis of SGLT2 and its network components' expression confidence identified selected organs in the following order: kidney, liver, adipose tissue, blood, heart, muscle, intestine, brain, and artery according to the TISSUES database. Drug repurposing analysis of known SGLT2i pointed out the influence of SGLT1 regulators on the heart and intestine tissue. Additionally, dapagliflozin seems to also have a stronger impact on brain tissue through the regulation of SGLT3 and SLC5A11. The shortest path analysis identified interaction SIRT1-SGLT2 among the top five interactions across six from seven analyzed networks associated with the key terms. Other top first-level SGLT2 interactors associated with key terms were not only ADIPOQ, INS, GLUT4, ACE, and GLUT1 but also less recognized ILK and ADCY7. Among other interactors which appeared in multiple shortest-path analyses were GPT, COG2, and MGAM. Enrichment analysis of SGLT2 network components showed the highest overrepresentation of hypertensive disease, DM-related diseases for both levels of SGLT2 interactors. Additionally, for the extended SGLT2 network, we observed enrichment in obesity (including SGLT1), cancer-related terms, neuroactive ligand-receptor interaction, and neutrophil-mediated immunity. This study provides comprehensive and ranked information about the SGLT2 interaction network in the context of tissue expression and can help to predict the clinical effects of the SGLT2i.

Transcatheter aortic valve implantation (TAVI) is an established treatment for aortic stenosis (AS) in patients at increased surgical risk. Up to 29% of patients annually experience major adverse cardiac and cerebrovascular events (MACCE) after TAVI. MicroRNAs (miRNA) are currently widely investigated as novel cardiovascular biomarkers. The aim of this study was to determine the influence of TAVI on the expressions of selected miRNAs associated with platelet function (miR-125a-5p, miR-125b and miR-223), and evaluate the predictive value of these miRNAs for MACCE in 65 patients undergoing TAVI.

Acute myocardial infarction (AMI) is the leading cause of morbidity and mortality worldwide. Damage to the endothelium is the earliest event in atherothrombosis, including AMI. Nitric oxide (NO), an endothelium-derived compound, protects the vasculature from damage. This study evaluated whether an association exists between plasma concentration of endogenous NO-related pathway metabolites linked to AMI and major adverse cardiovascular events (MACE) after AMI.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors present a class of antidiabetic drugs, which inhibit renal glucose reabsorption resulting in the elevation of urinary glucose levels. Within the past years, SGLT2 inhibitors have become increasingly relevant due to their effects beyond glycemic control in patients with type 2 diabetes (T2DM). Although dedicated large trials demonstrated cardioprotective effects of SGLT2 inhibitors, the exact mechanisms responsible for those benefits have not been fully identified. Alterations in Ca signaling and oxidative stress accompanied by excessive reactive oxygen species (ROS) production, fibrosis and inflammatory processes form cornerstones of potential molecular targets for SGLT2 inhibitors. This review focused on three hypotheses for SGLT2 inhibitor-mediated cardioprotection: ion homeostasis, oxidative stress and endothelial dysfunction.

To investigate the association of liver metabolite trimethylamine N-oxide (TMAO) with cardiovascular disease (CV)-related and all-cause mortality in patients with acute coronary syndrome (ACS) who underwent percutaneous coronary intervention. Our prospective observational study enrolled 292 patients with ACS. Plasma concentrations of TMAO were measured during the hospitalization for ACS. Observation period lasted seven yr in median. Adjusted Cox-regression analysis was used for prediction of mortality. ROC curve analysis revealed that increasing concentrations of TMAO levels assessed at the time point of ACS significantly predicted the risk of CV mortality (c-index=0.78, < 0.001). The cut-off value of >4 μmol/L, labeled as high TMAO level (23% of study population), provided the greatest sum of sensitivity (85%) and specificity (80%) for the prediction of CV mortality and was associated with a positive predictive value of 16% and a negative predictive value of 99%. A multivariate Cox regression model revealed that high TMAO level was a strong and independent predictor of CV death (HR = 11.62, 95% CI: 2.26-59.67; = 0.003). High TMAO levels as compared with low TMAO levels were associated with the highest risk of CV death in a subpopulation of patients with diabetes mellitus (27.3 vs. 2.6%; = 0.004). Although increasing TMAO levels were also significantly associated with all-cause mortality, their estimates for diagnostic accuracy were low. High TMAO level is a strong and independent predictor of long-term CV mortality among patients presenting with ACS.

This meta-analysis and systematic review was performed to evaluate the clinical relevance of subclinical leaflet thrombosis (SLT) following transcatheter aortic valve replacement. PubMed, Web of Science, and CENTRAL were searched for eligible randomized and nonrandomized studies until November 2020. Risk ratios (RRs) or odds ratios and 95% CIs were calculated, using a random-effects model. Overall, 25 studies were eligible for the analysis and comprised a total of 11,098 patients. The median incidence of SLT was 6% at a median follow-up of 30 days. Use of intra-annular valves was associated with 2-fold greater risk for the development of SLT compared with use of supra-annular valves. There was no difference in the risk for SLT (RR: 0.97; 95% CI: 0.72-1.29; P = 0.83) between single-antiplatelet therapy (SAPT) and dual-antiplatelet therapy (DAPT), whereas oral anticoagulation (OAC) was associated with a 58% relative risk reduction for SLT (RR: 0.42; 95% CI: 0.29-0.61; P < 0.00001) compared with SAPT and DAPT. In patients with diagnosed leaflet thrombosis at follow-up, the risk for stroke or transient ischemic attack was increased by 2.6-fold (RR: 2.56; 95% CI: 1.60-4.09; P < 0.00001) compared with patients without leaflet thrombosis. In patients diagnosed with SLT, the odds of SLT resolution increased by 99% after switch from antiplatelet agents to OAC (odds ratio: 0.01; 95% CI: 0.00-0.06; P < 0.00001). To summarize, indication-based use of OAC after transcatheter aortic valve replacement is associated with a lower risk for SLT compared with SAPT and DAPT. Switching to OAC seems to be effective for SLT resolution. As SLT increased the odds of stroke or transient ischemic attack in the included population, further studies are needed to investigate whether screening tests for SLT and appropriate antithrombotic therapy improve long-term valve functionality and clinical prognosis.

The impact of long-term training on cardiovascular disease (CVD) is not clear. Carotid intima-media thickness (CIMT) test is recommended as a useful measure to diagnose the early stages of atherosclerosis. MicroRNAs (miRNAs) are altered due to endurance exercise and can be promising biomarkers of pathophysiological changes. We aimed to evaluate the association of circulating miRNAs with physical fitness and markers of atherosclerosis in ultra-marathon runners. Ultra-marathon runners had 28-fold upregulation of miR-125a-5p expressions compared to control individuals ( = 0.002), whereas let-7e and miR-126 did not differ statistically between ultra-marathon runners and controls. In the ultra-marathon runners' group, negative correlations were observed between VOmax/kg and relative expression of miR-125a-5p and miR-126 (r = -0.402, = 0.028; r = -0.438, = 0.032, respectively). Positive correlations were observed between CIMT and miR-125a-5p and miR-126 (r = 0.388, = 0.050; r = 0.504, = 0.023, respectively) in ultra-marathon runners. Individuals with the highest quartile of VOmax/kg had 23-fold lower miR-126 expression in comparison to subgroups with lower VOmax/kg ( = 0.017). Our results may indicate that both miRNAs may serve as a biomarker for early pathological changes leading to atherosclerosis burden in athletes. Furthermore, the association between miRNAs and traditional risk factors for CVD indicate a possible use of these molecules as early biomarkers of future cardiovascular health.

Brain-derived neurotrophic factor (BDNF) is a member of the neurotrophin family of growth factors that plays a crucial role in the development of the nervous system while supporting the survival of existing neurons and instigating neurogenesis. Altered levels of BDNF, both in the circulation and in the central nervous system (CNS), have been reported to be involved in the pathogenesis of neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), Huntington's disease (HD), multiple sclerosis (MS), and ischemic stroke. MicroRNAs (miRNAs) are a class of non-coding RNAs found in body fluids such as peripheral blood and cerebrospinal fluid. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of neurodegenerative and neurovascular diseases. Thus, they present as promising biomarkers and a novel treatment approach for CNS disorders. Currently, limited studies provide viable evidence of miRNA-mediated post-transcriptional regulation of BDNF. The aim of this review is to provide a comprehensive assessment of the current knowledge regarding the potential diagnostic and prognostic values of miRNAs affecting BDNF expression and its role as a CNS disorders and neurovascular disease biomarker. Moreover, a novel therapeutic approach in neurodegenerative diseases and ischemic stroke targeting miRNAs associated with BDNF will be discussed.

Sodium-glucose co-transporter 2 (SGLT2) inhibitors are an emerging class of glucose-lowering drugs that have become increasingly relevant for the treatment and prevention of heart failure (HF). Therefore, we aimed to investigate various SGLT2 inhibitors in patients with established HF at baseline and focused on the different types of HF. An extensive search of PubMed and Web of Science until January 2021 was done. Two reviewers, independently and in duplicate, applied the selection criteria. This meta-analysis was conducted according to the PRISMA guidelines. Data were pooled using a random-effects model. Randomized controlled trials (RCTs) of SGLT2 inhibitors vs. a comparator in patients with HF reporting clinical outcomes were included. The primary efficacy outcome was the composite of hospitalization for HF (HHF) or cardiovascular (CV) mortality. All-cause mortality, CV mortality, and HHF were considered as secondary endpoints. Subgroup analyses involving the status of diabetes, type of HF, administered type of SGLT2 inhibitor, sex, age, body mass index (BMI), estimated glomerular filtration rate (eGFR), cause of HF, and concomitant medication were performed. Seventeen RCTs, comprising a total of 20,749 participants, were included ( = 10,848 treated with SGLT2 inhibitors and = 9,901 treated with a comparator). Treatment with SGLT2 inhibitors in a HF population was associated with a 27% relative risk reduction (RRR) of HHF or CV mortality [risk ratio (RR) = 0.73, 95% CI = 0.68-0.78], 32% RRR of HHF (RR = 0.68, 95% CI = 0.62-074), 18% RRR of CV mortality (RR = 0.82, 95% CI = 0.73-0.91), and 17% RRR of all-cause mortality (RR = 0.83, 95% CI = 0.75-0.91). The effect of SGLT2 inhibitors on the primary endpoint was consistent among the different gliflozines. The effect of SGLT2 inhibitors on the primary endpoint was independent of underlying diabetes mellitus, age, sex, BMI, renal function, and HF type. SGLT2 inhibitors are associated with improved CV outcomes in patients with HF.

Liver fibrosis results from an imbalance between extracellular matrix formation and degradation. The background of liver fibrosis is chronic inflammation and subsequent microcirculation disturbance including microthrombosis. Platelets actively participate in liver fibrosis not only as a part of the clotting system but also by releasing granules containing important mediators. In fact, platelets may play a dual role in the pathophysiology of liver fibrosis as they are able to stimulate regeneration as well as aggravate the destruction of the liver. Recent studies revealed that antiplatelet therapy correlates with inhibition of liver fibrosis. However, liver impairment is associated with extensive coagulation disorders thus the safety of antiplatelet therapy is an area for detailed exploration. In this review, the role of platelets in liver fibrosis and accompanying hemostatic disorders are discussed. Additionally, results of animal and human studies on antiplatelet drugs in liver disorders and their potential therapeutic utility are presented.

The epidemic of diabetes mellitus (DM) necessitates the development of novel therapeutic and preventative strategies to attenuate complications of this debilitating disease. Diabetic cardiomyopathy (DCM) is a frequent disorder affecting individuals diagnosed with DM characterized by left ventricular hypertrophy, diastolic and systolic dysfunction and myocardial fibrosis in the absence of other heart diseases. Progression of DCM is associated with impaired cardiac insulin metabolic signaling, increased oxidative stress, impaired mitochondrial and cardiomyocyte calcium metabolism, and inflammation. Various non-coding RNAs, such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs), as well as their target genes are implicated in the complex pathophysiology of DCM. It has been demonstrated that miRNAs and lncRNAs play an important role in maintaining homeostasis through regulation of multiple genes, thus they attract substantial scientific interest as biomarkers for diagnosis, prognosis and as a potential therapeutic strategy in DM complications. This article will review the different miRNAs and lncRNA studied in the context of DM, including type 1 and type 2 diabetes and the contribution of pathophysiological mechanisms including inflammatory response, oxidative stress, apoptosis, hypertrophy and fibrosis to the development of DCM .

Dual antiplatelet therapy (DAPT) and subsequent P2Y inhibitor monotherapy, particularly ticagrelor, is an emerging treatment strategy in patients undergoing percutaneous coronary intervention (PCI). This meta-analysis was designed to investigate whether short-term DAPT followed by ticagrelor monotherapy is associated with a favorable outcome as compared with standard DAPT (1-3 months of DAPT was termed "short-term" DAPT, 6-12 months DAPT was termed "standard" DAPT). The primary outcome was the composite of major adverse cardiovascular events (MACE) comprising myocardial infarction, stroke, and cardiovascular death. Secondary outcomes included all-cause mortality and net adverse clinical events (NACE; myocardial infarction, stroke, all-cause death, stent thrombosis, and major bleeding). The primary safety outcome was major bleeding. Three studies comprising 26,143 patients were included. The risk of MACE was similar between the two treatment groups (risk ratio (RR) 0.86, 95% confidence interval (CI), 0.72-1.02, P = 0.08, I  = 22%). Short-term DAPT followed by ticagrelor monotherapy resulted in a 20% relative risk reduction of all-cause mortality (RR 0.80, 95% CI, 0.65-0.98, P = 0.03, I  = 0%) and an 18% relative risk reduction of NACE (RR 0.82, 95% CI, 0.71-0.94, P = 0.005, I  = 33%) as compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy significantly decreased the risk of major bleeding (RR 0.67, 95% CI, 0.49-0.92, P = 0.01, I  = 65%). In patients with acute coronary syndrome, short-term DAPT followed by ticagrelor monotherapy resulted in an unchanged ischemic risk but a significantly lower bleeding risk compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy compared with standard DAPT resulted in a favorable safety and efficacy profile. Direct comparisons of aspirin vs. ticagrelor monotherapy following PCI are needed.

The ideal duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) is still unknown. In this meta-analysis, we aimed to compare very short-term (1-3 months), short-term (6 months), standard-term (12 months) and long-term (>12 months) DAPT durations for efficacy and safety.

The foundations of sports cardiology include promoting physical activity and an ability to provide a safe environment for training and competition for all athletes at all levels, from professional to recreational [...].

(1) Background: Prostacyclin analogues (epoprostenol, treprostinil, and iloprost) induce vasodilation in pulmonary arterial hypertension (PAH) but also inhibit platelet function. (2) Objectives: We assessed platelet function in PAH patients treated with prostacyclin analogues and not receiving prostacyclin analogues. (3) Methods: Venous blood was collected from 42 patients treated with prostacyclin analogues (49.5 ± 15.9 years, 81% female) and 38 patients not receiving prostacyclin analogues (55.5 ± 15.6 years, 74% female). Platelet reactivity was analyzed by impedance aggregometry using arachidonic acid (AA; 0.5 mM), adenosine diphosphate (ADP; 6.5 µM), and thrombin receptor-activating peptide (TRAP; 32 µM) as agonists. In a subset of patients, concentrations of extracellular vesicles (EVs) from all platelets (CD61), activated platelets (CD61/CD62P), leukocytes (CD45), and endothelial cells (CD146) were analyzed by flow cytometry. Platelet-rich thrombus formation was measured using a whole blood perfusion system. (4) Results: Compared to controls, PAH patients treated with prostacyclin analogues had lower platelet reactivity in response to AA and ADP ( = 0.01 for both), lower concentrations of platelet and leukocyte EVs ( ≤ 0.04), delayed thrombus formation ( ≤ 0.003), and decreased thrombus size ( = 0.008). Epoprostenol did not affect platelet reactivity but decreased the concentrations of platelet and leukocyte EVs ( ≤ 0.04). Treprostinil decreased platelet reactivity in response to AA and ADP ( ≤ 0.02) but had no effect on the concentrations of EVs. All prostacyclin analogues delayed thrombus formation and decreased thrombus size ( ≤ 0.04). (5) Conclusions: PAH patients treated with prostacyclin analogues had impaired platelet reactivity, EV release, and thrombus formation, compared to patients not receiving prostacyclin analogues.

Epicardial adipose tissue (EAT) volume is associated with cardiovascular disease (CVD). Data regarding the influence of extremely intensive training on CVD are scarce. We compared EAT volume among ultra-marathon runners and in the sedentary control group, and assessed the correlations between EAT and risk factors of coronary artery disease (CAD). EAT volume around three main coronary vessels and right ventricle (RV) was measured in 30 healthy amateur ultrarunners and 9 sex- and age-matched sedentary controls using cardiac magnetic resonance. In addition, body composition, lipid profile, interleukin-6 (IL-6) plasma concentration, and intima-media thickness (IMT) were measured as well. The EAT volume was lower in all measured locations in the ultrarunners' group compared to control group ( < 0.001 for all). Ultrarunners had lower BMI and fat percentage (FAT%) and more favorable lipid profile compared to the control group ( < 0.05 for all). Ultrarunners had lower rate of pathologically high levels of plasma IL-6 (>1 pg/mL) compared to the control group (17% vs. 56%, < 0.05). IMT was similar in both groups. In the ultrarunners' group, there was a positive correlation between EAT surrounding left anterior descending artery, circumflex artery, and RV and FAT%, and between EAT around circumflex artery and LDL and non-HDL cholesterol ( < 0.05 for all). In summary, extremely intensive training may decrease the risk of cardiovascular events in adult population of amateur athletes by reducing the amount and pro-inflammatory activity of EAT. However, more research is needed to draw firm conclusions regarding the anti- and pro-inflammatory effects of intensive training.

Background, the mechanisms underlying left ventricular remodelling (LVR) after acute myocardial infarction (AMI) remain obscure. In the course of AMI, blood cells and endothelial cells release extracellular vesicles (EVs). We hypothesized that changes in EV concentrations after AMI may underlie LVR. Methods, plasma concentrations of EVs from endothelial cells (CD146+), erythrocytes (CD235a+), leukocytes (CD45+), platelets (CD61+), activated platelets (P-selectin+), and EVs exposing phosphatidylserine after AMI were determined by flow cytometry in 55 patients with the first AMI. LVR was defined as an increase in left ventricular end-diastolic volume by 20% at 6 months after AMI, compared to baseline. Results, baseline concentrations of EVs from endothelial cells, erythrocytes and platelets were lower in patients who developed LVR ( ≤ 0.02 for all). Concentrations of EVs from endothelial cells and erythrocytes were independent LVR predictors (OR 8.2, CI 1.3-54.2 and OR 17.8, CI 2.3-138.6, respectively) in multivariate analysis. Combining the three EV subtypes allowed to predict LVR with 83% sensitivity and 87% specificity. Conclusions, decreased plasma concentrations of EVs from endothelial cells, erythrocytes and platelets predict LVR after AMI. Since EV release EVs contributes to cellular homeostasis by waste removal, decreased concentrations of EVs may indicate dysfunctional cardiac homeostasis after AMI, thus promoting LVR.

Dual antiplatelet therapy (DAPT) and subsequent P2Y inhibitor monotherapy, particularly ticagrelor, is an emerging treatment strategy in patients undergoing percutaneous coronary intervention (PCI). This meta-analysis was designed to investigate whether short-term DAPT followed by ticagrelor monotherapy is associated with a favorable outcome as compared with standard DAPT (1-3 months of DAPT was termed "short-term" DAPT, 6-12 months DAPT was termed "standard" DAPT). The primary outcome was the composite of major adverse cardiovascular events (MACE) comprising myocardial infarction, stroke, and cardiovascular death. Secondary outcomes included all-cause mortality and net adverse clinical events (NACE; myocardial infarction, stroke, all-cause death, stent thrombosis, and major bleeding). The primary safety outcome was major bleeding. Three studies comprising 26,143 patients were included. The risk of MACE was similar between the two treatment groups (risk ratio (RR) 0.86, 95% confidence interval (CI), 0.72-1.02, P = 0.08, I  = 22%). Short-term DAPT followed by ticagrelor monotherapy resulted in a 20% relative risk reduction of all-cause mortality (RR 0.80, 95% CI, 0.65-0.98, P = 0.03, I  = 0%) and an 18% relative risk reduction of NACE (RR 0.82, 95% CI, 0.71-0.94, P = 0.005, I  = 33%) as compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy significantly decreased the risk of major bleeding (RR 0.67, 95% CI, 0.49-0.92, P = 0.01, I  = 65%). In patients with acute coronary syndrome, short-term DAPT followed by ticagrelor monotherapy resulted in an unchanged ischemic risk but a significantly lower bleeding risk compared with standard DAPT. Short-term DAPT followed by ticagrelor monotherapy compared with standard DAPT resulted in a favorable safety and efficacy profile. Direct comparisons of aspirin vs. ticagrelor monotherapy following PCI are needed.

Elevations of hepatic transaminase (serum alanine transaminase [ALT] and serum aspartate aminotransferase [AST]) levels in patients with acute coronary syndrome (ACS), although transient, may result in exclusions from clinical efficacy trials due to suspected liver disease. The aim of this study was to evaluate the concentrations of serum transaminases in ACS and relate these to currently accepted AST/ALT exclusion criteria from clinical trials.

It is a matter of debate whether diabetes alone or its associated comorbidities are responsible for severe COVID-19 outcomes. This study assessed the impact of diabetes on intensive care unit (ICU) admission and in-hospital mortality in hospitalized COVID-19 patients.

Inflammation leads to atherosclerosis and acute coronary syndromes (ACS). We performed a prospective, observational study to assess association between the concentrations of inflammatory markers (high sensitivity C-reactive protein, hsCRP; high sensitivity interleukin6, hsIL-6; soluble CD40 ligand, sCD40 L) and platelet reactivity in 338 patients with ACS treated with ticagrelor and prasugrel. We also assessed whether hsCRP, hsIL-6, and sCD40 L are associated with standard inflammatory markers (white blood cell [WBC] and fibrinogen), and whether they differ according to patient diabetic status and pre-treatment with statins. Concentrations of hsCRP and concentrations of hsIL-6 and sCD40 L were assessed using turbidimetric assay and enzyme-linked immunosorbent assay, respectively. Platelet reactivity was measured using multiple electrode aggregometry. There was only a weak inverse correlation between hsIL-6 and platelet reactivity (r≤-0.125). In contrast, concentration of hsIL6 and hsCRP positively correlated with WBC and fibrinogen (r ≥ 0.199). Insulin-dependent diabetes mellitus (IDDM) was associated with higher concentration of hsIL-6 ( = .014), whereas pre-treatment with statins - with lower concentration of hsIL-6 ( = .035). In conclusion, inflammatory state does not affect the antiplatelet efficacy of potent P2Y12 inhibitors in the acute phase of ACS, confirming the safety and efficacy of potent P2Y12 inhibitors in patients with a high inflammatory burden.

Noncoding RNAs (ncRNAs), including long noncoding RNAs and microRNAs, play an important role in coronary artery disease onset and progression. The ability of ncRNAs to simultaneously regulate many target genes allows them to modulate various key processes involved in atherosclerosis, including lipid metabolism, smooth muscle cell proliferation, autophagy, and foam cell formation. This review focuses on the therapeutic potential of the most important ncRNAs in coronary artery disease. Moreover, various other promising microRNAs and long noncoding RNAs that attract substantial scientific interest as potential therapeutic targets in coronary artery disease and merit further investigation are presented.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (coronavirus disease 2019; COVID-19) is associated with adverse outcomes in patients with cardiovascular disease (CVD). The aim of the study was to characterize the interaction between SARS-CoV-2 and Angiotensin-Converting Enzyme 2 (ACE2) functional networks with a focus on CVD.

Platelet extracellular vesicles (PEVs) are potential new biomarkers of platelet activation which may allow us to predict and/or diagnose developing coronary thrombosis before myocardial necrosis occurs. The P2Y1 and P2Y12 receptors play a key role in platelet activation and aggregation. Whereas the P2Y1 antagonists are at the preclinical stage, at present, the P2Y12 antagonists are the most effective treatment strategy to prevent stent thrombosis after percutaneous coronary intervention. Despite an increasing number of publications on PEVs, the mechanisms underlying their formation, including the role of purinergic receptors in this process, remain an active research field. Here, we outline the clinical relevance of PEVs in cardiovascular disease, summarize the role and downstream signalling of P2Y receptors in platelet activation, and discuss the available evidence regarding their role in PEV formation.

Diabetes mellitus (DM) is a common disease worldwide. There is a strong association between DM and neurovascular and neurodegenerative disorders. The first group mainly consists of diabetic retinopathy, diabetic neuropathy and stroke, whereas, the second group includes Alzheimer's disease, Parkinson's disease, mild cognitive impairment and dementia. The aforementioned diseases have a common pathophysiological background including insulin resistance, oxidative stress, atherosclerosis and vascular injury. The increasing prevalence of neurovascular and neurodegenerative disorders among diabetic patients has resulted in an urgent need to develop biomarkers for their prediction and/or early detection. The aim of this review is to present the potential application of the most promising biomarkers of diabetes-related neurodegenerative and neurovascular disorders, including amylin, β-amyloid, C-reactive protein (CRP), dopamine, gamma-glutamyl transferase (GGT), glycogen synthase kinase 3β, homocysteine, microRNAs (mi-RNAs), paraoxonase 1, phosphoinositide 3-kinases, tau protein and various growth factors. The most clinically promising biomarkers of neurovascular and neurodegenerative complications in DM are hsCRP, GGT, homocysteine and miRNAs. However, all biomarkers discussed in this review could become a part of the potential multi-biomarker screening panel for diabetic patients at risk of neurovascular and neurodegenerative complications.

Activated platelets contribute to thrombosis and inflammation by the release of extracellular vesicles (EVs) exposing P-selectin, phosphatidylserine (PS) and fibrinogen. P2Y12 receptor antagonists are routinely administered to inhibit platelet activation in patients after acute myocardial infarction (AMI), being a combined antithrombotic and anti-inflammatory therapy. The more potent P2Y12 antagonist ticagrelor improves cardiovascular outcome in patients after AMI compared to the less potent clopidogrel, suggesting that greater inhibition of platelet aggregation is associated with better prognosis. The effect of ticagrelor and clopidogrel on the release of EVs from platelets and other P2Y12-exposing cells is unknown. This study compares the effects of ticagrelor and clopidogrel on (1) the concentrations of EVs from activated platelets (primary end point), (2) the concentrations of EVs exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells (secondary end points) and (3) the procoagulant activity of plasma EVs (tertiary end points) in 60 consecutive AMI patients. After the percutaneous coronary intervention, patients will be randomized to antiplatelet therapy with ticagrelor (study group) or clopidogrel (control group). Blood will be collected from patients at randomization, 48 hours after randomization and 6 months following the index hospitalization. In addition, 30 age- and gender-matched healthy volunteers will be enrolled in the study to investigate the physiological concentrations and procoagulant activity of EVs using recently standardized protocols and EV-dedicated flow cytometry. Concentrations of EVs will be determined by flow cytometry. Procoagulant activity of EVs will be determined by fibrin generation test. The compliance and response to antiplatelet therapy will be assessed by impedance aggregometry. We expect that plasma from patients treated with ticagrelor (1) contains lower concentrations of EVs from activated platelets, exposing fibrinogen, exposing PS, from leukocytes and from endothelial cells and (2) has lower procoagulant activity, when compared to patients treated with clopidogrel. Antiplatelet therapy effect on EVs may identify a new mechanism of action of ticagrelor, as well as create a basis for future studies to investigate whether lower EV concentrations are associated with improved clinical outcomes in patients treated with P2Y12 antagonists.

Our study aims to perform a meta-analysis of benefits and risks associated with the use of non-vitamin K oral anticoagulants (NOAC) versus vitamin K antagonists (VKA) in patients with a percutaneous coronary intervention (PCI) with a particular focus on the combination type: dual vs. dual antithrombotic therapy (DAT: NOAC + single antiplatelet therapy (SAPT) vs. DAT: VKA + SAPT), dual vs. triple antithrombotic therapy (DAT: NOAC + SAPT vs. TAT: VKA + dual antiplatelet therapy (DAPT)) or triple vs. triple antithrombotic therapy (TAT: NOAC+DAPT vs. TAT: VKA+DAPT).

To investigate the long-term clinical benefit of dual antiplatelet therapy with potent P2Y12 inhibitors compared to clopidogrel in patients with acute coronary syndrome (ACS).

In recent years, ischemic stroke (IS) has been one of the major causes of disability and mortality worldwide. The general mechanism of IS is based on reduced blood supply to neuronal tissue, resulting in neuronal cell damage by various pathological reactions. One of the main techniques for acute IS treatment entails advanced surgical approaches for restoration of cerebral blood supply but this is often associated with secondary brain injury, also known as ischemic reperfusion injury (I/R injury). Many researches have come to emphasize the significant role of long non-coding RNAs (lncRNAs) in IS, especially in I/R injury and their potential as therapeutic approaches. LncRNAs are non-protein transcripts that are able to regulate cellular processes and gene expression. Further, lncRNAs have been shown to be involved in neuronal signaling pathways. Several lncRNAs are recognized as key factors in the physiological and pathological processes of IS. In this review, we discuss the role of lncRNAs in neuronal injury mechanisms and their association with brain neuroprotection. Moreover, we identify the lncRNAs that show the greatest potential as novel therapeutic approaches in IS, which therefore merit further investigation in preclinical research. Graphical Abstract.

The interleukin-6 (IL-6) pathway has a crucial role in the pathogenesis of atherosclerosis, the main cause of cardiovascular diseases. We aimed to characterize the predictive value of inflammatory biomarkers on long-term cardiovascular mortality in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI).

Diabetes mellitus (DM) is a complex condition and serious health problem, with growing occurrence of DM-associated complications occurring globally. Persistent hyperglycemia is confirmed as promoting neurovascular dysfunction leading to irreversible endothelial cell dysfunction, increased neuronal cell apoptosis, oxidative stress and inflammation. These collaboratively and individually result in micro- and macroangiopathy as well as neuropathy demonstrated by progressive neuronal loss. Recently, major efforts have been pursued to select not only useful diagnostic and prognostic biomarkers, but also novel therapeutic approaches. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) belong to a class of non-coding RNAs identified in most of the body fluids i.e., peripheral blood, cerebrospinal fluid, brain tissue and neurons. Numerous miRNAs, lncRNAs and their target genes are able to modulate signaling pathways known to play a role in the pathophysiology of progressive neuronal dysfunction. Therefore, they pose as promising biomarkers and treatment for the vast majority of neurodegenerative disorders. This review provides an overall assessment of both miRNAs' and lncRNAs' utility in decelerating progressive nervous system impairment, including neurodegeneration in diabetic pathways.

To investigate the long-term clinical benefit of dual antiplatelet therapy with potent P2Y12 inhibitors compared to clopidogrel in patients with acute coronary syndrome (ACS).

Endurance sports have an unarguably beneficial influence on cardiovascular health and general fitness. Regular physical activity is considered one of the most powerful tools in the prevention of cardiovascular disease. MicroRNAs are small particles that regulate the post-transcription gene expression. Previous studies have shown that miRNAs might be promising biomarkers of the systemic changes in response to exercise, before they can be detected by standard imaging or laboratory methods. In this review, we focused on four important physiological processes involved in adaptive changes to various endurance exercises (namely, cardiac hypertrophy, cardiac myocyte damage, fibrosis, and inflammation). Moreover, we discussed miRNAs' correlation with cardiopulmonary fitness parameter (VO). After a detailed literature search, we found that miR-1, miR-133, miR-21, and miR-155 are crucial in adaptive response to exercise.

 von Willebrand factor (VWF) is crucial for arterial thrombosis and its plasma levels are increased in acute coronary syndromes (ACSs). The effects of conventional platelet inhibitors are compromised by elevated VWF under high shear rates. BT200 is a third-generation aptamer that binds and inhibits the A1 domain of human VWF. This article aims to study whether VWF is a predictor of mortality in ACS patients under potent P2Y12 blocker therapy and to examine the effects of a VWF inhibiting aptamer BT200 and its concentrations required to inhibit VWF in plasma samples of patients with ACS.

Diabetes mellitus (DM) is a common disease worldwide. There is a strong association between DM and neurovascular and neurodegenerative disorders. The first group mainly consists of diabetic retinopathy, diabetic neuropathy and stroke, whereas, the second group includes Alzheimer's disease, Parkinson's disease, mild cognitive impairment and dementia. The aforementioned diseases have a common pathophysiological background including insulin resistance, oxidative stress, atherosclerosis and vascular injury. The increasing prevalence of neurovascular and neurodegenerative disorders among diabetic patients has resulted in an urgent need to develop biomarkers for their prediction and/or early detection. The aim of this review is to present the potential application of the most promising biomarkers of diabetes-related neurodegenerative and neurovascular disorders, including amylin, β-amyloid, C-reactive protein (CRP), dopamine, gamma-glutamyl transferase (GGT), glycogen synthase kinase 3β, homocysteine, microRNAs (mi-RNAs), paraoxonase 1, phosphoinositide 3-kinases, tau protein and various growth factors. The most clinically promising biomarkers of neurovascular and neurodegenerative complications in DM are hsCRP, GGT, homocysteine and miRNAs. However, all biomarkers discussed in this review could become a part of the potential multi-biomarker screening panel for diabetic patients at risk of neurovascular and neurodegenerative complications.

Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets, leukocytes, and endothelial cells release proinflammatory and prothrombotic extracellular vesicles (EVs), we hypothesized that the release of EVs is more efficiently inhibited by ticagrelor compared to clopidogrel.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are established antidiabetic drugs with proven cardiovascular benefit. Although growing evidence suggests beneficial effects on myocardial remodeling, fluid balance and cardiac function, the impact of empagliflozin initiated early after acute myocardial infarction (AMI) has not been investigated yet. Therefore, the impact of EMpagliflozin on cardiac function and biomarkers of heart failure in patients with acute MYocardial infarction (EMMY) trial was designed to investigate the efficacy and safety of empagliflozin in diabetic and non-diabetic patients after severe AMI.

Intensive and prolonged exercise leads to a rise of troponin concentration in blood. The mechanism responsible for troponin release during exercise remains ill-defined. The study aim was to search for risk factors of troponin increase after a prolonged endurance competition.

Platelet extracellular vesicles (PEVs) are potential new biomarkers of platelet activation which may allow us to predict and/or diagnose developing coronary thrombosis before myocardial necrosis occurs. The P2Y1 and P2Y12 receptors play a key role in platelet activation and aggregation. Whereas the P2Y1 antagonists are at the preclinical stage, at present, the P2Y12 antagonists are the most effective treatment strategy to prevent stent thrombosis after percutaneous coronary intervention. Despite an increasing number of publications on PEVs, the mechanisms underlying their formation, including the role of purinergic receptors in this process, remain an active research field. Here, we outline the clinical relevance of PEVs in cardiovascular disease, summarize the role and downstream signalling of P2Y receptors in platelet activation, and discuss the available evidence regarding their role in PEV formation.

Type 2 diabetes mellitus (T2DM) is a common metabolic disorder, which carries a risk for atherosclerosis and cardiovascular impairment. The purpose of this review is to demonstrate the role of acetylsalicylic acid (ASA) in primary cardiovascular prevention in T2DM patients, as well as present an outline of microRNAs (miRNA) relevant to ASA therapy and should be evaluated as targets to improve treatment.

Out-of-hospital cardiac arrest is among the most frequent causes of death worldwide. Immediate intervention, as well as dual antiplatelet therapy consisting of acetylsalicylic acid and a P2Y inhibitor is often recommended. In line with the growing number of reports on cardiac arrest treatment, therapeutic hypothermia (TH) has been proposed for unconscious patients to improve neurological outcomes. Nevertheless, studies report controversial and often discrepant results on the effect of hypothermia on blood coagulability and platelet reactivity. In this review, we summarize the knowledge on platelet function under diverse hypothermic conditions. Additionally, we review the current literature on the effect of systemic hypothermia on pharmacokinetic and pharmacodynamic properties of antiplatelet agents. It has been shown that TH can alter the effectiveness of antiplatelet agents, including P2Y inhibitors, through multiple mechanisms, hence, special attention should be paid while implementing antiplatelet therapy in patients under TH conditions.

In the light of growing global epidemic of type 2 diabetes mellitus (T2DM), significant efforts are made to discover next-generation biomarkers for early detection of the disease. Multiple mechanisms including inflammatory response, abnormal insulin secretion and glucose metabolism contribute to the development of T2DM. Platelet activation, on the other hand, is known to be one of the underlying mechanisms of atherosclerosis, which is a common T2DM complication that frequently results in ischemic events at later stages of the disease. Available data suggest that platelets contain large amounts of microRNAs (miRNAs) that are found in circulating body fluids, including the blood. Since miRNAs have been illustrated to play an important role in metabolic homeostasis through regulation of multiple genes, they attracted substantial scientific interest as diagnostic and prognostic biomarkers in T2DM. Various miRNAs, as well as their target genes are implicated in the complex pathophysiology of T2DM. This article will first review the different miRNAs studied in the context of T2DM and platelet reactivity, and subsequently present original results from bioinformatic analyses of published reports, identifying a common gene (PRKAR1A) linked to glucose metabolism, blood coagulation and insulin signalling and targeted by miRNAs in T2DM. Moreover, miRNA-target gene interaction networks built upon Gene Ontology information from electronic databases were developed. According to our results, miR-30a-5p, miR-30d-5p and miR-30c-5p are the most widely regulated miRNAs across all specified ontologies, hence they are the most promising biomarkers of T2DM to be investigated in future clinical studies.

The aim of this study was to investigate the association of serum brain-derived neurotrophic factor (BDNF) levels with platelet reactivity and antidiabetes treatment, as well as serum adipocytokine concentrations.

Percutaneous coronary interventions with stent-based restorations of vessel patency have become the gold standard in the treatment of acute coronary states. Bioresorbable vascular scaffolds (BVS) have been designed to combine the efficiency of drug-eluting stents (DES) at the time of implantation and the advantages of a lack of foreign body afterwards. Complete resolution of the scaffold was intended to enable the restoration of vasomotor function and reduce the risk of device thrombosis. While early reports demonstrated superiority of BVS over DES, larger-scale application and longer observation exposed major concerns about their use, including lower radial strength and higher risk of thrombosis resulting in higher rate of major adverse cardiac events. Further focus on procedural details and research on the second generation of BVS with novel properties did not allow to unequivocally challenge position of DES. Nevertheless, BVS still have a chance to present superiority in distinctive indications. This review presents an outlook on the available first and second generation BVS and a summary of results of clinical trials on their use. It discusses explanations for unfavorable outcomes, proposed enhancement techniques and a potential niche for the use of BVS.

Platelet P2Y receptors play a key role in platelet activation and thrombus formation. Accordingly, P2Y receptor antagonists are the cornerstone of secondary prevention of atherothrombotic events in patients undergoing percutaneous coronary intervention (PCI). The availability of different oral P2Y antagonists (clopidogrel, prasugrel, ticagrelor) along with the introduction of the first intravenous P2Y antagonist cangrelor offer an opportunity to individualize antiplatelet therapy according to the changing clinical setting. The recent International Expert Consensus provided the first recommendations on switching between the P2Y antagonists. While the consensus greatly helps to guide switching between P2Y antagonists, a number of controversial clinical scenarios remain where the evidence regarding the optimal switch strategy is scarce. In such clinical scenarios, understanding of the (i) pharmacological properties of P2Y antagonists, (ii) recent evidence from pharmacodynamics studies, clinical trials and registries, and (iii) factors affecting the efficacy and safety of the P2Y antagonists, all summarized below, are crucial to choose the optimal switch strategy.

The role of aspirin in primary prevention of cardiovascular disease (CVD) remains unclear. We aimed to investigate the benefit-risk ratio of aspirin for primary prevention of CVD with a particular focus on subgroups.

Aortic valve tissue is largely exposed to high blood flow. Cells belonging to aortic valve tissues are able to detect and respond to flow conditions changes. Bicuspid aortic valve (BAV) presents altered morphology, with only two abnormal cusps instead of three. This results in an alteration of blood flow dynamics on valve cusps and aortic wall, which may, in turn, increase the risk to develop aortic stenosis and/or regurgitation, endocarditis, aortopathy and/or aortic dissection. MicroRNAs (miRNAs) are short RNA strands regulating gene expression mainly through the inhibition of their target mRNAs. They are largely involved in cardiovascular pathophysiology and heart disease. More recently, it has been observed that the expression of specific miRNAs can be modulated in response to changes in hemodynamic conditions. Using a bioinformatic approach, this article analyses available scientific evidence about the differential expression of miRNAs in the bicuspid aortic valve, with a focus on the differential modulation compared to the calcific-degenerative tricuspid aortic valve.

The impact of rare and damaging variants in genes associated with platelet function in large‑vessel ischemic stroke (LVIS) remains unknown. The aim of this study was to investigate the contribution of some of these variants to the genetic susceptibility to LVIS in Polish patients using a deep re‑sequencing of 54 selected genes, coding for proteins associated with altered platelet function. Targeted pooled re‑sequencing (Illumina HiSeq 2500) was performed on genomic DNA of 500 cases (patients with history of clinically proven diagnosis of LVIS) and 500 age‑, smoking status‑, and sex‑matched controls (no history of any type of stroke), and from the same population as patients with LVIS. After quality control and prioritization based on allele frequency and damaging probability, individual genotyping of all deleterious rare variants was performed in patients from the original cohort, and stratified to concomitant cardiac conditions differing between the study and stroke groups. We demonstrated a statistically significant increase in the number of rare and potentially damaging variants in some of the investigated genes in the LVIS pool (an increase in the genomic variants burden). Furthermore, we identified an association between LVIS and 6 rare functional and damaging variants in the Kv7.1 potassium channel gene (KCNQ1). The predicted functional properties (partial loss‑of function) for the three most damaging variants in KCNQ1 coding locus were further confirmed in vitro by analyzing the membrane potential changes in cell lines co‑transfected heterogeneously with human muscarinic type 1 receptor and wild‑type or mutated KCNQ1 cDNA constructs using fluorescence imaging plate reader. The study demonstrated an increased rare variants burden for 54 genes associated with platelet function, and identified a putative role for rare damaging variants in the KCNQ1 gene on LVIS susceptibility in the Polish population.

Antiplatelet therapy with P2Y receptor inhibitors (clopidogrel, prasugrel, ticagrelor, cangrelor) is a cornerstone of medical therapy after percutaneous coronary interventions. Significant prevalence of high on-treatment platelet reactivity (HTPR) on clopidogrel treatment led to introduction of more potent P2Y inhibitors: prasugrel (a third generation thienopyridine), ticagrelor, and cangrelor (cyclopentyl-triazolo-pyrimidines). Nevertheless, more potent platelet inhibition and resulting low on-treatment platelet reactivity (LTPR) has led to increased risk of major bleeding events. These limitations resulted in a need for an individualized antiplatelet therapy approach. This review discusses the current role and future perspectives of diagnostic tools such as platelet function testing to optimize antiplatelet therapy with a focus on deescalating therapies to reduce bleeding risks.

Stroke is the second-most common cause of death worldwide. The pathophysiology of ischemic stroke (IS) is related to inflammation, atherosclerosis, blood coagulation, and platelet activation. MicroRNAs (miRNAs) play important roles in physiological and pathological processes of neurodegenerative diseases and progression of certain neurological diseases, such as IS. Several different miRNAs, and their target genes, are recognized to be involved in the pathophysiology of IS. The capacity of miRNAs to simultaneously regulate several target genes underlies their unique value as diagnostic and prognostic markers in IS. In this review, we focus on the role of miRNAs as diagnostic and prognostic biomarkers in IS. We discuss the most common and reliable detection methods available and promising tests currently under development. We also present original results from bioinformatic analyses of published results, identifying the ten most significant genes (HMGB1, YWHAZ, PIK3R1, STAT3, MAPK1, CBX5, CAPZB, THBS1, TNFRSF10B, RCOR1) associated with inflammation, blood coagulation, and platelet activation and targeted by miRNAs in IS. Additionally, we created miRNA-gene target interaction networks based on Gene Ontology (GO) information derived from publicly available databases. Among our most interesting findings, miR-19a-3p is the most widely modulated miRNA across all selected ontologies and might be proposed as novel biomarker in IS to be tested in future studies.

Dual antiplatelet therapy is the standard of care for patients with myocardial infarction (MI), who have been resuscitated and treated with therapeutic hypothermia (TH). We compare the antiplatelet effect and bleeding risk of intravenous cangrelor to oral P2Y12-inhibitors in patients with MI receiving TH in a prospective comparison of two matched patient cohorts. Twenty-five patients within the CANGRELOR cohort were compared to 17 patients receiving oral P2Y12-inhibitors. CANGRELOR group (NCT03445546) and the ORAL P2Y12 Group (NCT02914795) were registered at clinicaltrials.gov. Platelet function testing was performed using light-transmittance aggregometry and monitored for 4 days. P2Y12-inhibition was stronger in CANGRELOR compared to ORAL P2Y12 (adenosine diphosphate (ADP) (area under the curve (AUC)) 26.0 (5.9⁻71.6) vs. 160.9 (47.1⁻193.7)) at day 1. This difference decreased over the following days as more patients were switched from CANGRELOR to oral P2Y12-inhibitor treatment. There was no difference in the effect of aspirin between the two groups. We did not observe significant differences with respect to thrombolysis in myocardial infarction (TIMI) or Bleeding Academic Research Consortium (BARC) classified bleedings, number of blood transfusions or drop in haemoglobin B (Hb) or hematocrit (Hct) over time. Cangrelor treatment is not only feasible and effective in resuscitated patients, but also inhibited platelet function more effectively than orally administered P2Y12-inhibitors without an increased event rate for bleeding.

The majority of resuscitated patients present with underlying cardiac disease, and out of these myocardial infarction is most common. Immediate interventional treatment is recommended and routinely requires dual antiplatelet therapy including aspirin and a P2Y12-inhibitor. Therapeutic hypothermia or target temperature management is also recommended in these patients. Cardiogenic shock as well as reduced body temperature impacts platelet reactivity and its medical inhibition. The study aims to quantify aspirin- and P2Y12-mediated platelet inhibition in patients presenting with myocardial infarction and cardiopulmonary resuscitation. Twenty-five resuscitated patients were enrolled in this prospective, observational, non-randomized single-centre study. These patients were compared to 77 matched controls from the ATLANTIS-ACS database of non-resuscitated patients with myocardial infarction. Platelet function testing was performed by light transmittance aggregometry. Aspirin reactivity was monitored by inducing platelet aggregation with collagen and arachidonic acid, respectively. P2Y12 inhibition was recorded by stimulation of platelet aggregation with adenosine diphosphate. To quantify the overall platelet response, thrombin receptor-activated peptide was used. Aspirin-mediated platelet reactivity decreased significantly in resuscitated patients during the first days and was significantly weaker on day 3 (collagen AUC 253.8 (122.7-352.2) vs. 109.0 (73.0-182.0); p = 0.022). P2Y12-mediated platelet inhibition was also impaired in resuscitated patients on day 3 (mean ADP AUC (IQR): CPR 172.1 (46.7-346.5) vs. control 43.9 (18.9-115.2); p < 0.05). Aspirin- and P2Y12-mediated platelet inhibition is impaired in resuscitated patients treated with therapeutic hypothermia. On day 3, we recorded lowest inhibitory effects of both drug types and patients might be at particular risk at that time. Potentially, intravenous aspirin and P2Y12 inhibitors might still supply a more predictable and stable platelet inhibition.

Platelet hyperactivity has been implicated in many cardiovascular (CV) events such as ischemic stroke, myocardial infarction and CV death. Genetic variability of platelet receptors has been shown to impact Src family kinases (SFKs) activation and in turn influence platelet activation. SFKs are important signal transmitters in platelets, interacting with several receptors as GPIIB/IIIa, GPIb, PEAR 1, GPIa, GPVI, PECAM and CD148.

Novel antiplatelet drugs, including ticagrelor, are being successively introduced into the therapy of atherothrombotic conditions due to their superiority over a standard combination of clopidogrel with acetylsalicylic acid in patients with acute coronary syndromes (ACS). A P2Y12 receptor antagonist, ticagrelor, is unique among antiplatelet drugs, because ticagrelor inhibits the platelet P2Y12 receptor in a reversible manner, and because it demonstrates a wide palette of advantageous pleiotropic effects associated with the increased concentration of adenosine. The pleiotropic effects of ticagrelor comprise cardioprotection, restoration of the myocardium after an ischemic event, promotion of the release of anticoagulative factors and, eventually, anti-inflammatory effects. Beyond the advantageous effects, the increased concentration of adenosine is responsible for some of ticagrelor's adverse effects, including dyspnea and bradycardia. Large-scale clinical trials demonstrated that both standard 12-month therapy and long-term use of ticagrelor reduce the risk of cardiovascular events in patients with ACS, but at the expense of a higher risk of major bleeding. Further trials focused on the use of ticagrelor in conditions other than ACS, including ischemic stroke, peripheral artery disease and status after coronary artery bypass grafting. The results of these trials suggest comparable efficacy and safety of ticagrelor and clopidogrel in extra-coronary indications, but firm conclusions are anticipated from currently ongoing studies. Here, we summarize current evidence on the superiority of ticagrelor over other P2Y12 antagonists in ACS, discuss the mechanism underlying the drug-drug interactions and pleiotropic effects of ticagrelor, and present future perspectives of non-coronary indications for ticagrelor.

Platelet activation plays a pivotal role in the development and progression of atherosclerosis, which often leads to potentially fatal ischemic events at later stages of the disease. Platelets and platelet microvesicles (PMVs) contain large amounts of microRNA (miRNA), which contributes largely to the pool of circulating miRNAs. Hence, they represent a promising option for the development of innovative diagnostic biomarkers, that can be specific for the underlying etiology. Circulating miRNAs can be responsible for intracellular communication and may have a biological effect on target cells. As miRNAs associated to both cardiovascular diseases (CVD) and diabetes mellitus can be measured by means of a wide array of techniques, they can be exploited as an innovative class of smart disease biomarkers. In this manuscript, we provide an outline of miRNAs associated with platelet function and reactivity (miR-223, miR-126, miR-197, miR-191, miR-21, miR-150, miR-155, miR-140, miR-96, miR-98) that should be evaluated as novel biomarkers to improve diagnostics and treatment of CVD.