Ticagrelor and prasugrel are key antiplatelet agents used in patients with acute coronary syndrome (ACS) undergoing percutaneous coronary intervention (PCI). Beyond their antiplatelet effects, both drugs exhibit pleiotropic actions that may contribute to side effects. Notably, ticagrelor has been associated with dyspnea in clinical trials. This study aimed to identify metabolomic markers linked to the effects of ticagrelor and prasugrel using targeted metabolomics. Plasma samples from 207 ACS patients treated with either prasugrel (n = 106) or ticagrelor (n = 101) were analyzed for up to 631 metabolites. Several metabolites differed significantly between the groups (p < 0.05). The most notable changes were found in DHEAS (p = 0.0004, FC = -1.66) and 3-Met-His (p = 0.0024, FC = 1.75). After adjusting for risk factors, lysoPC a C17:0, 3-Met-His, and DHEAS remained significantly altered. Subgroup analysis revealed that diabetic patients had distinct metabolic profiles, including elevated TMAO and choline and reduced GUDCA levels, compared to non-diabetics. Additional changes were observed in hexoses, Met-SO, and TCDCA. The findings support a novel hypothesis that ticagrelor-induced dyspnea may be linked to low DHEAS levels. Reduced methionine and Met-SO levels could suggest lower oxidative stress. Moreover, diabetic patients showed a gut microbiome-related metabolic shift associated with a more ischemic profile.

This Delphi-derived expert consensus provides a clinical framework to optimize and maintain healthspan along the lifespan from the cardiometabolic health perspective in both healthy individuals and individuals with well-controlled cardiometabolic diseases. The framework guides the shaping of the evidence base in the clinical approach for assessing and targeting intrinsic capacity and healthspan. This approach integrates well-established cardiometabolic guidelines with the innovative and rapidly developing field of healthspan medicine. Recommendations were developed through a literature review and structured Delphi consensus. To ensure methodological rigor, recommendations were developed using a grading framework adapted from AHA/ESC guidelines. This system applied standardized Classes of Recommendation (I, IIa-c, III) and added novel Class IIc to designate interventions with uncertain or minimal benefit, supported by limited or inconclusive evidence. Evidence levels ranged from multiple RCTs/meta-analyses (A) to single RCTs or non-RCT studies (B) to expert consensus (C). Such an approach is a crucial step toward building both evidence and credibility for clinical strategies aimed at preserving healthspan-specifically by preventing cardiometabolic pathological aging and the associated decline in intrinsic capacity. The healthspan-oriented care framework defines healthy aging from a cardiometabolic perspective, classifying individuals into "healthy aging without CMD" and "healthy aging with well-controlled CMD" based on clinical, laboratory, and functional criteria. The framework also evaluates emerging diagnostic tools and their role in risk stratification. While emerging approaches show considerable promise, their clinical translation requires further validation, standardization, and large-scale evidence. This Delphi-derived expert consensus outlines a comprehensive framework for the cardiometabolic healthspan-oriented model of care by integrating evidence-based clinical criteria, functional assessments, and emerging geroscience insights.

Introduction and Objective: SGLT2 inhibitors, primarily used for type 2 diabetes, exhibit cardioprotective effects by improving myocardial metabolism, reducing oxidative stress, and modulating inflammation and fibrosis—key factors in acute myocardial infarction (AMI). This study explores the molecular mechanisms of SGLT2 inhibitors, focusing on non-coding RNAs and sirtuin pathways, to identify biomarkers and strategies for preventing heart failure post-AMI. Methods: We analyzed microRNAs (miRNAs) involved in sirtuin pathways and validated miRNA and sirtuin gene expressions (SIRT1-7) in 243 patients at baseline and after 26 weeks of treatment (486 samples) using qRT-PCR. We also conducted SHAP analysis, miRNA target predictions, and enrichment analyses. Results: Bioinformatics identified interaction networks for SGLT2 (5225 nodes) and SIRT1-7 (top 100 interactors), annotated for oxidative stress, inflammation, fibrosis, and hypoxia-ischemia. Combining miRNA predictions with these networks identified 13 key miRNAs, including hsa-miR-34a-5p, miR-182-5p, and hsa-miR-302a-3p, targeting SIRT and SGLT2-related pathways. Empagliflozin treatment significantly increased SIRT6, SIRT7, and miR-34a while reducing SIRT4 (p<0.05). Baseline SIRT2 and SIRT4 levels independently predicted unfavorable LVEF outcomes (AUC: 0.655, p=0.002), with improved prediction using a panel including miR-182-5p (AUC: 0.786, p=0.0003). NT-proBNP levels were higher in the unfavorable group after 26 weeks, but no baseline differences were observed. Conclusion: Empagliflozin modulates sirtuin and miRNA expression, suggesting cardioprotective effects in AMI. Baseline SIRT2, SIRT4, and miR-182-5p levels predict unfavorable LVEF outcomes, with a combined biomarker panel offering high accuracy. These findings highlight the potential of integrating sirtuins, miRNAs, and clinical biomarkers for improved cardiac outcome management post-AMI. A. Nowak-Szwed: Speaker's Bureau; Novo Nordisk. C. Eyileten: None. Z. Wicik: None. S. Ahmadova: None. J. Siller-Matula: None. D. von Lewinski: Speaker's Bureau; Daiichi Sankyo, Novo Nordisk. Research Support; Merck Sharp & Dohme Corp. H. Sourij: Advisory Panel; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Research Support; Eli Lilly and Company. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Daiichi Sankyo. Advisory Panel; Novo Nordisk A/S. Speaker's Bureau; Novo Nordisk A/S. Advisory Panel; Novartis AG, Amarin Corporation, Amgen Inc. M. Postula: None. EMPATHYtrial 2019/ABM/01/00037NCN 2022/45/N/NZ7/0246

Background: Percutaneous coronary intervention (PCI) is a widely used treatment strategy for coronary artery disease. Optimal long-term antithrombotic therapy after PCI remains challenging. Objectives: This substudy of the Vienna PCI Registry assessed long-term effects of direct oral anticoagulant (DOAC) use on major adverse cardiac events (MACEs) in patients with chronic coronary syndrome (CCS) after PCI, exploring possible pleiotropic effects. Methods: We analyzed patients with CCS from the Vienna PCI Registry treated with a drug-eluting stent (DES) between 2015 and 2020. The primary end point was clinically driven target lesion revascularization (TLR). The secondary composite end point (MACE) included TLR, target vessel revascularization (TVR), stent thrombosis (ST), and all-cause death. Patients received either triple antithrombotic therapy (TAT; DOAC, aspirin, and clopidogrel), followed by DOAC monotherapy, or dual antiplatelet therapy (DAPT; aspirin and clopidogrel), followed by single antiplatelet therapy. Results: Among 1046 patients with CCS, 176 (16.8%) received TAT followed by DOAC monotherapy. The primary end point TLR occurred significantly less often in TAT-treated patients (2.8% vs 8.4%). MACE rates were similar between TAT and DAPT groups (17.0% vs 17.0%). All-cause mortality was higher in the TAT group (11.9% vs 7.8%). Multivariable regression showed that TAT followed by DOAC monotherapy was associated with a reduced 5-year risk of TLR compared with DAPT followed by single antiplatelet therapy (odds ratio, 0.367; 95% CI, 0.147-0.917; P =.032). Conclusion: Patients treated with TAT demonstrated a statistically significant risk decrease for the primary end point clinically driven TLR in the elective CCS-PCI setting at 5 years' follow-up, which may be in part due to pleiotropic effects of DOACs.

The purpose of this study was to evaluate the properties and pharmacokinetics of liposomal vitamin C in powder form obtained by a method devoid of organic solvents. The powder and liposome morphology were analyzed using scanning electron microscopy (SEM) and cryogenic transmission electron microscopy (cryo-TEM), respectively. Additionally, the carrier particle size, size distribution (STEP-Technology®; L.U.M. GmbH, Berlin, Germany), and zeta potential value were determined. The pharmacokinetic parameters of liposomal and non-liposomal vitamin C (AUC, Cmax, C10h, and C24h) were compared in a randomized, single-dose, double-blind, cross-over trial (ClinicalTrials.gov ID: NCT05843617) involving healthy adult volunteers (n = 10, 1000 mg dose). The process of spray drying used to transform liquid suspensions of the liposomes into powder form did not adversely affect the quality of the carrier particles obtained. Compared to non-encapsulated vitamin C, oral administration of the liposomal formulation resulted in significantly better absorption of ascorbic acid into the bloodstream, which equated to a higher bioavailability of the liposomal product (30% increase in AUC, p < 0.05). The duration of elevated vitamin C blood levels was also longer (C24h increase of 30%, p < 0.05). Although the results obtained are promising and suggest higher bioavailability for the liposomal form of vitamin C, the limited sample size necessitates further research with a larger cohort to confirm these findings.

Introduction/Background: Platelet P2Y12 antagonist ticagrelor reduces mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Research Question/Hypothesis: The research question focuses on predictive analysis of drug response to P2Y12 inhibitors in patients with AMI prior to the initiation of treatment. Aim of the Study: In the present study, we aimed to investigate the metabolic profiles of plasma samples from AMI patients to identify potential disease biomarkers and to study patients after AMI treated with ticagrelor or clopidogrel. Methods: Twenty-two (22) patients with the first AMI were randomized to ticagrelor or clopidogrel. Plasma samples were obtained at three time points (24 hours, 72 hours, and 6 months) from AMI patients. Metabolic profiles of the plasma of 22 AMI patients and 11 controls (longitudinal sample size (N) = 77) were obtained, and over 1000 plasma metabolites were assayed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). The Aligned Rank Transform (ARTool) R package was used as a nonparametric equivalent to the multi-factorial repeated measures analysis of variance (ANOVA) and post hoc analysis. Results: Trigonelline from the alkaloid group of metabolites was identified as a uniquely affected metabolite in paired comparisons for AMI patients. After 6 months, trigonelline levels were higher in patients on ticagrelor compared to those on ticagrelor at 72 hours after the switch and those on clopidogrel at 24 hours (p.adjusted (p.adj) = 0.017, p.adj = 0.038, respectively). Other affected groups of metabolites included triacylglycerols (TAGs) and triglycerides (TGs). Up and down-regulated metabolites are presented in Figure 1. Glycolithocholic acid sulfate (GLCAS) and Citrulline were upregulated, while TG was downregulated in clopidogrel group compared to ticagrelor group. phospholipids were found to be significantly lower in the AMI patients compared to control group (p<0.001, see Figure 2). Conclusion: Our study showed that increasing levels of the trigonelline metabolite are associated with long-term response to ticagrelor treatment. Trigonelline is a product of niacin metabolism and a common plant alkaloid that has been shown to reduce platelet aggregation. It acts by affecting β-cell regeneration, insulin secretion, activities of enzymes related to glucose metabolism, reactive oxygen species (ROS), axonal extension, and neuron excitability.

Leaflet thrombosis (LT) is a multifaceted and underexplored condition that can manifest following transcatheter aortic valve implantation (TAVI). The objective of this study was to formulate a prediction model based on laboratory assessments and clinical parameters, providing additional guidance and insight into this relatively unexplored aspect of post-TAVI complications. The present study was an observational prospective hypothesis-generating study, including 101 patients who underwent TAVI and a screening for LT (the primary endpoint) by multidetector computed tomography (MDCT). All images were acquired on a third-generation dual-source CT system. Levels of von Willebrand factor (vWF) activity, hemoglobin (Hb), and lactate dehydrogenase (LDH) were measured among other parameters. A predictive score utilizing binary logistic regression, Kaplan–Meier time-to-event analysis, and receiver operating characteristics (ROC) analysis was established. LT (11 subclinical and 2 clinical) was detected in 13 of 101 patients (13

Sodium-glucose cotransporter 2 (SGLT2, SLC5A2) is a promising target for a new class of drug primarily established as kidney-targeting as well as emerging class of glucose-lowering drugs in diabetes. Studies showed that SGLT2 inhibitors also have a systemic impact via indirectly targeting the heart and kidneys which exerts broad cardio- and nephroprotective effects. Additionally, as cancer cells tightly require glucose supply, studies also questioned how SGLT2 inhibitors impact molecular pathology and cellular metabolism in cancer hallmarks. However, the exact molecular mechanisms responsible for those benefits have not been fully discovered. MicroRNAs (miRNA) and circularRNAs (circRNAs) are endogenous, single-stranded, non-coding RNAs (ncRNAs) that can control protein-coding genes, affecting significant molecular and cellular processes regulating homeostasis. CircRNAs particularly regulate gene expression at the transcriptional and post-transcriptional level by sponging to miRNAs and by altering interactions between proteins.

Angiotensin converting enzyme 2 (ACE2) serves as the primary receptor for the SARS-CoV-2 virus and has implications for the functioning of the cardiovascular system. Based on our previously published bioinformatic analysis, in this study we aimed to analyze the diagnostic and predictive utility of miRNAs (miR-10b-5p, miR-124-3p, miR-200b-3p, miR-26b-5p, miR-302c-5p) identified as top regulators of ACE2 network with potential to affect cardiomyocytes and cardiovascular system in patients with COVID-19. The expression of miRNAs was determined through qRT-PCR in a cohort of 79 hospitalized COVID-19 patients as well as 32 healthy volunteers. Blood samples and clinical data of COVID-19 patients were collected at admission, 7-days and 21-days after admission. We also performed SHAP analysis of clinical data and miRNAs target predictions and advanced enrichment analyses. Low expression of miR-200b-3p at the seventh day of admission is indicative of predictive value in determining the length of hospital stay and/or the likelihood of mortality, as shown in ROC curve analysis with an AUC of 0.730 and a p-value of 0.002. MiR-26b-5p expression levels in COVID-19 patients were lower at the baseline, 7 and 21-days of admission compared to the healthy controls (P < 0.0001). Similarly, miR-10b-5p expression levels were lower at the baseline and 21-days post admission (P = 0.001). The opposite situation was observed in miR-124-3p and miR-302c-5p. Enrichment analysis showed influence of analyzed miRNAs on IL-2 signaling pathway and multiple cardiovascular diseases through COVID-19-related targets. Moreover, the COVID-19-related genes regulated by miR-200b-3p were linked to T cell protein tyrosine phosphatase and the HIF-1 transcriptional activity in hypoxia. Analysis focused on COVID-19 associated genes showed that all analyzed miRNAs are strongly affecting disease pathways related to CVDs which could be explained by their strong interaction with the ACE2 network.

Abstract Background GLP1R analogs are drugs increasingly used in clinical practice in patients with type 2 diabetes, and obesity. Subsequent clinical trials indicate their beneficial effects, including cardioprotection, but the exact mechanisms of those actions are still not known. Aim of the study: This study aims to understand how GLP1R analogs exert cardioprotective and therapeutic effects in patients with type 2 diabetes and obesity. Through analyzing GLP1R interaction networks and associated metabolomic and lipidomic data, we seek to uncover the molecular mechanisms underlying these effects and their potential therapeutic implications. Methods We performed an integrative analysis of four GLP1Ri interaction networks and associated metabolomic and lipidomic datasets. Interactomics revealed 130 common genes among semaglutide, exenatide, tirzapeptide, and retatrutide, primarily associated with diabetes-related processes, including obesity and hyperglycemia. Noteworthy findings encompassed ontological terms related to cardiovascular diseases (CVDs), such as hypertension, calcium regulation in cardiac cells, and amino acid accumulation-induced mTOR activation. Additionally, enrichment in gene sets linked to longevity, less recognized terms like fatty liver disease, chemokine signaling, and sirtuin interactome, were observed. Results Specific processes for tirzepatide included behavior-related terms and hydrochloric acid secretion, while retatrutide exhibited associations with fibrosarcoma, thinking and speaking disturbances, and adipogenesis signaling. Shared processes like primary ciliary dyskinesia differed in implicated genes. Metabolomics identified shared metabolites associated with diverse pathways, including galactose metabolism and nitric oxide-related pathways. Lipidomics highlighted enriched phenotypes and pathways, such as arachidonic acid metabolism and cholesterol biosynthesis. Conclusion Integration of interaction networks with metabolomic and lipidomic data revealed top interactors and impacted metabolites, shedding light on the intricate molecular landscape of GLP1Ri. These findings contribute valuable insights into the potential therapeutic implications and broader health considerations of GLP1R drugsfig1fig2

Objective: Women have a higher comorbidity burden and a lower survival rate after acute myocardial infarction (AMI) than men. This analysis aimed to investigate the impact of sex on the effect of treatment with the sodium glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin immediately after an AMI. Methods: Participants were randomized to either empagliflozin or placebo and followed for 26 weeks after initiating the treatment no later than 72 hours after a percutaneous coronary intervention following an AMI. We analyzed the impact of sex on the beneficial effects of empagliflozin observed for heart failure biomarkers as well as structural and functional cardiac parameters. Results: Women had higher NT-proBNP levels at baseline (median 2117pg/mL, IQR 1383-3267 pg/mL versus 1137 pg/mL, IQR 695-2050 pg/mL; p < 0.001) and were older than men (median 61y, IQR 56-65y versus 56y, IQR 51-64y, p = 0.005). The beneficial effects of empagliflozin on NT-proBNP levels (P-interaction = 0.984), left ventricular ejection fraction (P-interaction = 0.812), left ventricular end systolic volume (P-interaction = 0.183), or left ventricular end diastolic volume (P-interaction = 0.676) were independent of sex. Conclusions: Empagliflozin exhibited similar benefits in women and men when administered immediately after an AMI.

Besides a significant reduction in major adverse cardiovascular events, the EMPA-REG outcome trial has shown a reduced risk for cardiovascular death and hospitalizations for heart failure compared with placebo in people with type 2 diabetes (T2D) treated with the sodium-glucose cotransporter 2 inhibitor (SGLT2i) empagliflozin.1 The EMPEROR trials showed a similar risk reduction for cardiovascular death or hospitalization for heart failure in patients with chronic heart failure, both with preserved and reduced ejection fraction, when treated with empagliflozin, irrespective of the glycaemic status of the study participants.2, 3 Furthermore, the empagliflozin in acute myocardial infarction (EMMY) trial showed beneficial effects of empagliflozin treatment on the N-terminal prohormone of brain natriuretic peptide (NT-proBNP) as well as functional and structural cardiac parameters when treatment was initiated immediately after an acute myocardial infarction (AMI).4 As previous data suggest that dysglycaemia is very common in people with coronary artery disease or MI,5, 6 this post-hoc analysis of the EMMY trial aims to investigate whether the observed beneficial cardiac effects depend on the baseline glycaemic status of the participants. This is a post hoc subgroup analysis of the EMMY trial. Details of the EMMY study design and the primary outcome have been published previously.4, 7 Briefly, the EMMY trial was a multicentre, randomized (1:1 ratio), double-blind and placebo-controlled trial, which investigated the effect of empagliflozin (10 mg once daily), administered for 26 weeks, on heart failure biomarkers and cardiac function metrices when initiated immediately (within 72 h) after AMI. The enrolled participants who underwent percutaneous coronary intervention after an AMI, were 18-80 years of age, haemodynamically stable and had a blood pressure >110/70 mmHg. Patients with other types of diabetes than T2D, a blood pH value of <7.32, haemodynamic instability, acute urinary tract or genital infections, on current SGLT2i treatment, or having received SGLT2i treatment within 4 weeks before enrolment were excluded from the trial. The EMMY trial was approved by the ethics committee of the Medical University of Graz, Austria (EK 29-179 ex16/17, EudraCT 2016-004591-22) and registered at ClinicalTrials.gov (NCT03087773). The trial performance conformed to the 1964 Declaration of Helsinki and adhered to the guidelines of Good Clinical Practice (ICH GCP E6). In this prespecified secondary analysis, we investigated the impact of glycaemic status on treatment effects and potential differences in trajectories of NT-proBNP levels as well as structural and functional cardiac parameters following AMI. Three categories of glycaemic status were compared: normoglycaemia, prediabetes and T2D. Participants were classified as normoglycaemic if the glycated haemoglobin (HbA1c) levels during admission for the AMI were <5.7% (<39 mmol/mol). Prediabetes was defined as an HbA1c of 5.7%-6.4% (39-47 mmol/mol) without glucose-lowering medication. Patients were classified as having T2D in case of previous glucose-lowering medication and/or an HbA1c of >6.4% (>47 mmol/mol) at enrolment. Continuous variables were reported as mean ± standard deviation or median with interquartile range (IQR) and categorical variables as frequency with percentage. The impact of the glycaemic status on the empagliflozin treatment effect on cardiac markers was assessed using multiple linear regression models adjusting for traditional risk factors, including age, sex and baseline NT-proBNP levels. For each cardiac marker the modification effect of glycaemic status was investigated by adding an interaction term between treatment and glycaemic status into the multiple linear regression model. All statistical analyses were performed using R software version 4.1.0. (https://www.r-project.org). Values for p < .05 were considered statistically significant according to glycaemic status. In 456 of the overall 476 participants randomized in the EMMY trial, HbA1c levels were available during the hospitalization for AMI; 63 (13.8%) had established T2D, 158 (34.7%) prediabetes and 235 (51.5%) were considered normoglycaemic, respectively. The percentage of people with obesity increased gradually from the normoglycaemic to the T2D category, as did hypertension. HbA1c levels were 5.4% (IQR 5.3%-5.5%) in the normoglycaemic group, 5.9% (IQR 5.7-6.0%) in those with prediabetes and 6.8% (6.4%-8.3%) in the T2D group, respectively. NT-proBNP levels and left ventricular ejection fraction did not differ between the three groups. Table 1 provides the full set of baseline characteristics. The EMMY trial reported for the overall study population, which meant NT-proBNP over 26 weeks was 15% (95% confidence interval −4.4% to −23.6%) lower with empagliflozin compared with placebo after adjusting for baseline NT-proBNP, sex and diabetes status in the main analysis. The impact of empagliflozin on the changes in NT-proBNP levels from baseline to week 26 was not found to be dependent of glycaemic status at baseline (pinteraction .133 and .582 for the comparison of prediabetes vs. normoglycaemic and T2D vs. normoglycaemia, respectively). Table 2 provides details of the analysis of the secondary echocardiography-based study outcomes for interaction with the three glycaemic groups. Only for the left ventricular ejection fraction, a significant interaction effect (pinteraction = .032) is found when comparing prediabetes with normoglycaemia suggesting a less pronounced effect in people with prediabetes. No such interaction is observed for people with T2D compared with those with normoglycaemia. Within the EMMY trial, impaired glucose metabolism is present in 48.5% of patients admitted to the hospital for AMI. However, the current subgroup analysis shows similar effects of empagliflozin treatment in all glycaemic groups on NT-proBNP levels as well as structural and functional parameters of cardiac function, when the treatment is initiated immediately after an AMI. A number of reasons for these beneficial findings were discussed previously, including inflammation.8 However, in the EMMY trial we observed a significant reduction in inflammatory markers after the AMI but without an impact of the empagliflozin treatment.9 While there is one significant interaction for left ventricular ejection fraction between the prediabetes and normoglycaemia group, suggesting a more pronounced improvement in the latter group with empagliflozin treatment, we would refrain from overemphasizing this finding with a pinteraction of .032. As we performed 10 interaction analyses and none of the other parameters showed a similar signal, this observed interaction might be even by chance. Our results, however, are in line with previous analyses showing similar beneficial effects of empagliflozin across the spectrum of glycaemia in people with heart failure and reduced3 or preserved10 ejection fraction. The EMMY study was no cardiovascular outcome trial and used the heart failure surrogate marker NT-proBNP as the primary outcome. The recently published DAPA-MI trial investigating the SGLT2i dapagliflozin in patients with MI, showed an improvement in cardiometabolic outcomes but without improvement in the composite of heart failure hospitalizations or cardiovascular death compared with placebo.11 In the EMMY trial, the SGLT2i treatment with empagliflozin was initiated in all participants within 72 h after the acute event, while the DAPA-MI trial allowed for up to 10 days after a preceding AMI. The cardiovascular outcome trial of empagliflozin in people with AMI is still ongoing (NCT04509674).12 Another limitation of the trial is that we did not perform oral glucose tolerance tests; hence, the prevalence of people with prediabetes or diabetes based on post-challenge hyperglycaemia might be even higher than the one observed. In this prespecified subgroup analysis of the EMMY trial, empagliflozin significantly improved NT-proBNP and echocardiographic structural and functional parameters largely irrespective of the baseline glycaemic status of the participants. HS and DvL designed the study; AO and F Aziz analysed the data; F Aberer, TP, NJT, PNP, HD, MB, EK and HB conducted the trial and/or collected the data; and CS wrote the first draft of the manuscript. All authors read and revised the manuscript carefully. We would like to thank all the participants of the EMMY trial. The EMMY trial was funded by an investigator-initiated study grant to HS. HS is on the speakers' bureau and/or the advisory board of Amgen, Amarin, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, K:businesscom, NovoNordisk and Sanofi. All other authors have no conflicts of interest to declare. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15477. Data is available upon reasonable request to the principal investigators.

Introduction: Studies have demonstrated direct cardio-protective effect of SGLT2 inhibitors, but the mechanism of action is unclear. We hypothesize that cardioprotective effects of SGLT2 inhibitors are due to increased expressions of Sirtuins and their regulator-miRNAs. Method: We conducted in silico prediction analysis using a computational approach. We identified/ranked the most promising ncRNAs associated with sirtuin pathways and SGLT2. We identified top miRNAs by preparing a gene list of all SIRT genes, 1st and 2nd level SGLT2 interactors, and genes involved in inflammation, fibrosis, oxidative stress, hypoxia-ischemia, MI and HF based on DisGeNet database. We validated our findings through qRT-PCR using selected plasma samples (empagliflozin/placebo=24/24; baseline, 26-weeks after treatment) collected from the double-blinded EMMY clinical trial (NCT03087773). Results: Our in silico analysis identified six miRNAs; miR-34a-5p, miR-27a-3p, miR-302a-3p, miR-146a-5p, miR-182-5p and miR-124-3p, which target the highest number of SIRT1-7 genes, SGLT2 and first-level SGLT2 interactors. qRT-PCR analysis showed that after 26 weeks of treatment, patients taking empagliflozin had significantly higher expression of miR-214 (p=0,015), miR-34a (p<0,001), miR-146a (p<0,001), miR-182-5p (p<0,001) and SIRT2 (p=0,005) compared to baseline. We also found that patients taking empagliflozin had significantly higher expression of SIRT6 (p=0,036), and significantly lower expression of miR-214 (p=0,007) and miR-302a-3p (p=0,042) compared to placebo. Conclusion: Our in silico analysis for the first time predicted the interaction network between ncRNAs and HF-related genes in the context of the SGLT2-sirtuin axis. We showed based on our prediction, empagliflozin, an SGLT2 inhibitor, can demonstrate cardioprotective effects via SIRT2 and SIRT6 and their ncRNA regulators axis. Disclosure A. Nowak: None. Z. Wicik: None. C. Eyileten: None. S. Ahmadova: None. J. Siller-Matula: None. D. von Lewinski: Speaker's Bureau; AstraZeneca. Research Support; Novo Nordisk. H. Sourij: Advisory Panel; Amarin Corporation. Speaker's Bureau; Amgen Inc., Amarin Corporation, Bayer Inc. Advisory Panel; Boehringer-Ingelheim. Speaker's Bureau; Boehringer-Ingelheim. Research Support; Boehringer-Ingelheim. Advisory Panel; Eli Lilly and Company. Research Support; Eli Lilly and Company. Speaker's Bureau; Eli Lilly and Company. Advisory Panel; Novartis AG. Speaker's Bureau; Novartis AG. Advisory Panel; Novo Nordisk. Research Support; Novo Nordisk. Speaker's Bureau; Novo Nordisk. Research Support; Sanofi. Speaker's Bureau; Sanofi. Consultant; K:Businesscom. M. Postula: None. Funding Polish National Scientific Centre (2022/45/N/NZ7/02461); Polish Medical Research Agency (2019/ABM/01/00037)

BACKGROUND:Platelet P2Y12 antagonist ticagrelor reduces cardiovascular mortality after acute myocardial infarction (AMI) compared to clopidogrel, but the underlying mechanism is unknown. Because activated platelets release proatherogenic and proinflammatory microRNAs, including miR-125a, miR-125b and miR-223, we hypothesized that the expression of these miRNAs is lower on ticagrelor, compared to clopidogrel. OBJECTIVES:We compared miR-125a, miR-125b and miR-223 expression in plasma of patients after AMI treated with ticagrelor or clopidogrel. METHODS:After percutaneous coronary intervention on acetylsalicylic acid and clopidogrel, 60 patients with first AMI were randomized to switch to ticagrelor or to continue with clopidogrel. Plasma expression of miR-223, miR-125a-5p, miR-125b was measured using quantitative polymerase chain reaction at baseline and after 72 h and 6 months of treatment with ticagrelor or clopidogrel in patients and one in 30 healthy volunteers. Multiple electrode aggregometry using ADP test was used to determine platelet reactivity in response to P2Y12 inhibitors. RESULTS:Expression of miR-125b was higher in patients with AMI 72 h and 6 months, compared to healthy volunteers (p = 0.001), whereas expression of miR-125a-5p and miR-223 were comparable. In patients randomized to ticagrelor, expression of miR-125b decreased at 72 h (p = 0.007) and increased back to baseline at 6 months (p = 0.005). Expression of miR-125a-5p and miR-223 was not affected by the switch from clopidogrel to ticagrelor. CONCLUSIONS:Ticagrelor treatment leads to lower plasma expression of miR-125b after AMI, compared to clopidogrel. Higher expression of miR-125b might explain recurrent thrombotic events and worse clinical outcomes in patients treated with clopidogrel, compared to ticagrelor.

Introduction:Plasma concentrations of gut microbial metabolites are associated with cardiomyocyte viability and platelet reactivity. We hypothesized that increased concentrations of gut metabolites may predict major adverse cardiac and cerebrovascular events (MACCE) after acute myocardial infarction (AMI). Aim:The primary objective of this study was to evaluate the association between elevated plasma concentrations of gut metabolites and MACCE after AMI. Material and methods:We compared plasma concentrations of gut metabolites (trimethylamine-N-oxide (TMAO) and indoxyl sulphate (IS)) and platelet reactivity in 57 patients with AMI and 27 healthy controls. We assessed the predictive value of gut metabolites for MACCE (stroke, recurrent AMI, death) over a median of 3.5-years. Results:The concentrations of TMAO and IS did not differ between AMI patients and controls. The concentrations of TMAO and IS were higher in patients who developed MACCE than in those who did not (p ≤ 0.015 for all). The concentration of TMAO was the only independent predictor of MACCE in a multivariate analysis (OR = 35.041, 95% CI: 1.269-967.307, p = 0.036). Patients with the concentration of TMAO and indoxyl sulphate above the cut-off value predictive of MACCE had higher platelet activity (p ≤ 0.149 for all). Conclusions:Increased plasma concentration of TMAO is an independent predictor of MACCE and may contribute to post-AMI cardiac dysfunction.

Regular physical exercise increase longevity, however acute intensive/longterm exercise can trigger the CV pathophysiological processes. Ultramarathon runners' plasma (n=22) with 2time points: before and after the run: Completion (100km) or exhaustion (median74km) was used for analysis. For untargeted metabolomic analysis; ultrahigh resolution MassSpectrometry with electrospray ion source in direct injection used and analyzed by T-Rex2D algorithm. Identified compounds analyzed using MetaboAnalystR/MetscapeCytoscape plugin was used for metabolite-gene interaction analysis, identifying 1601 up and 1030 downregulated metabolites with min 2 fold difference after ultramarathon run Enrichment analysis showed that TCA cycle (FDR=0.0442), metabolism of; Sphingolipids (p=0.008), Glyoxylate and dicarboxylate (p=0.03) and Butanoate (p=0.04) were the top metabolites. After the run top upregulated metabolites were related to heart failure associated metabolites; acetylcarnitines2 CAR(14:2) (AUC=0.97) Dodecanoylcarnitine (2.00;0.960), 9-Decenoylcarnitine (1.78;0.95), CAR(DC8:0) (14.99;0.94), 2Carboxy5,7dimethyl4octanolide (8.04;0.98), Methylmalonic acid (9.33;0.96) and cardiotoxic Cyclophosphamide (16.29;0.940). Top downregulated metabolites after the run included potentially cardioprotective Gamma Glutamylglutamic acid (log2FC=-1.81;AUC=0.85), Fructose 1,6bisphosphate (-2.42;0.88)4, Oleamide (-1.82;0.86) and gammaGlutamylglycine (-7.98;0.85).Interaction network analysis showed genes associated with atherosclerosis/obesity-related PhospholipaseA2,IB (PLA2G1B) as potentially the most affected gene by analyzed metabolites. Twofold post run increase in metabolites showed they are both potential markers for acute exercise and are strongly associated with CV diseases. This calls for consideration of the detrimental effects of excessive exercise and implementation of monitoring in amateur athletes.

W ostatnich latach wyzwaniem stała się terapia pacjentów z zespołem metabolicznym, który jest czynnikiem ryzyka powikłań sercowo-naczyniowych. Obiecującym kierunkiem badań w kontekście pacjentów z łagodnym przerostem gruczołu krokowego oraz ze współistniejącym zespołem metabolicznym okazała się doksazosyna – selektywny antagonista receptorów α-adrenergicznych. Opracowano nowy preparat doksazosyny w postaci doustnego systemu terapeutycznego w celu poprawy profilu farmakokinetycznego oraz zmniejszenia lub wyeliminowania konieczności dostosowywania dawki i ryzyka przedawkowania. Zgodnie z aktualnymi wytycznymi doksazosyna zajmuje ważną pozycję w leczeniu opornego nadciśnienia tętniczego.

Background: Oxygen uptake (VO2) is one of the most important measures of fitness and critical vital sign. Cardiopulmonary exercise testing (CPET) is a valuable method of assessing fitness in sport and clinical settings. There is a lack of large studies on athletic populations to predict VO2max using somatic or submaximal CPET variables. Thus, this study aimed to: (1) derive prediction models for maximal VO2 (VO2max) based on submaximal exercise variables at anaerobic threshold (AT) or respiratory compensation point (RCP) or only somatic and (2) internally validate provided equations. Methods: Four thousand four hundred twenty-four male endurance athletes (EA) underwent maximal symptom-limited CPET on a treadmill (n=3330) or cycle ergometer (n=1094). The cohort was randomly divided between: variables selection (nrunners = 1998; ncyclist = 656), model building (nrunners = 666; ncyclist = 219), and validation (nrunners = 666; ncyclist = 219). Random forest was used to select the most significant variables. Models were derived and internally validated with multiple linear regression. Results: Runners were 36.24±8.45 years; BMI = 23.94 ± 2.43 kg·m−2; VO2max=53.81±6.67 mL·min−1·kg−1. Cyclists were 37.33±9.13 years; BMI = 24.34 ± 2.63 kg·m−2; VO2max=51.74±7.99 mL·min−1·kg−1. VO2 at AT and RCP were the most contributing variables to exercise equations. Body mass and body fat had the highest impact on the somatic equation. Model performance for VO2max based on variables at AT was R2=0.81, at RCP was R2=0.91, at AT and RCP was R2=0.91 and for somatic-only was R2=0.43. Conclusions: Derived prediction models were highly accurate and fairly replicable. Formulae allow for precise estimation of VO2max based on submaximal exercise performance or somatic variables. Presented models are applicable for sport and clinical settling. They are a valuable supplementary method for fitness practitioners to adjust individualised training recommendations. Funding: No external funding was received for this work.

Abstract Background Ischemic stroke (IS) is one of the most frequent causes of death. Since miRNAs have been illustrated to play an important role in various processes through regulation of multiple genes, and platelet function, their utility as novel biomarkers should be determined. We aimed to identify and validate circulating miRNAs, modulated in acute ischemic stroke (IS) patients in order to distinguish the most specific as biomarkers to facilitate diagnosis and prognosis. Method Sixty patients with acute IS (24-h and 7-days after IS) and 30 age- and gender-matched individuals free of stroke with multiple risk factors for cardiovascular disease. Studied miRNAs were selected based on bioinformatic analysis that was previously published by our team (1-2-3). PlasmaRNA was extracted; quality RNA was assessed: fluorometric assay; RT-PCR for miRNAs expression measurement p<0.05. Results Let-7e expression 7-day of IS was significantly lower than both controls and first day of IS (p=0.007, p=0.001, res). miR-125a-3p was lower both at day-1 and day-7 of IS compared to controls (p=0.008, p=0.020, res). miR-125a-5p on the other hand, had significantly higher expression at day-1 compared to controls (p=0.002). Both miR-125a-3p and -5p showed diagnostic value in ROC curve analysis (AUC= 0.705, AUC= 0.709, res). Patients with moderate stroke (based on NIHSS) had significantly higher miR-16-5p expression levels compared to patients with minor stroke at the first day of IS (AUC: 0.718, (95% CI, 0.59-0.85) p = 0.004). High baseline expression of miR-16-5p and diabetes mellitus are independent predictors of increased severity of stroke to a multivariate analysis (OR: 4.341; 95% CI, 1.15–16.42; p = 0.031 and OR: 4.653; 95% CI, 1.07–20.19; p = 0.040, res). Conclusion In this study we validated miRNAs based on our previous bioinformatic analysis which could serve as novel, platelet-related predictive biomarkers of the IS severity, and can be used for early stratification of patients and prediction of severity of disease development in an individual.