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Background and Aims: Cardiogenic shock (CS) remains the primary cause of in-hospital death after acute coronary syndromes (ACS), with its plateauing mortality rates approaching 50%. To test novel interventions, personalized risk prediction is essential. The ORBI (Observatoire Régional Breton sur l'Infarctus) score represents the first-of-its-kind risk score to predict in-hospital CS in ACS patients undergoing percutaneous coronary intervention (PCI). However, its sex-specific performance remains unknown, and refined risk prediction strategies are warranted., Methods: This multinational study included a total of 53 537 ACS patients without CS on admission undergoing PCI. Following sex-specific evaluation of ORBI, regression and machine-learning models were used for variable selection and risk prediction. By combining best-performing models with highest-ranked predictors, SEX-SHOCK was developed, and internally and externally validated., Results: The ORBI score showed lower discriminative performance for the prediction of CS in females than males in Swiss (area under the receiver operating characteristic curve [95% confidence interval]: 0.78 [0.76-0.81] vs. 0.81 [0.79-0.83]; P =.048) and French ACS patients (0.77 [0.74-0.81] vs. 0.84 [0.81-0.86]; P = .002). The newly developed SEX-SHOCK score, now incorporating ST-segment elevation, creatinine, C-reactive protein, and left ventricular ejection fraction, outperformed ORBI in both sexes (females: 0.81 [0.78-0.83]; males: 0.83 [0.82-0.85]; P < .001), which prevailed following internal and external validation in RICO (females: 0.82 [0.79-0.85]; males: 0.88 [0.86-0.89]; P < .001) and SPUM-ACS (females: 0.83 [0.77-0.90], P = .004; males: 0.83 [0.80-0.87], P = .001)., Conclusions: The ORBI score showed modest sex-specific performance. The novel SEX-SHOCK score provides superior performance in females and males across the entire spectrum of ACS, thus providing a basis for future interventional trials and contemporary ACS management., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Continuously improving cancer-specific survival puts a growing proportion of cancer patients at risk of major adverse cardiovascular events (MACE), but tailored tools for cardiovascular risk prediction remain unavailable., Objectives: To assess a broad panel of cardiovascular biomarkers and risk factors for the prediction of MACE and cardiovascular death in cancer patients., Methods: In total, 2192 patients with newly diagnosed or recurrent cancer were followed prospectively for the occurrence of 2-year MACE and 5-year cardiovascular death. Univariable and multivariable risk models were fit to assess independent associations of cardiovascular risk factors and biomarkers with adverse outcomes, and a risk score was developed., Results: Traditional cardiovascular risk factors and selected cancer types were linked to higher MACE risk. While levels of Lp(a), CRP, and GDF-15 did not associate with MACE, levels of ICAM-1, P-/E-/L-selectins, and NT-proBNP were independently linked to 2-year MACE risk. A clinical risk score was derived, assigning +1 point for male sex, smoking, and age of ≥60 years and +2 points for atherosclerotic disease, yielding a bootstrapped C-statistic of 0.76 (95% CI: 0.71-0.81) for the prediction of 2-year MACE. Implementation of biomarker data conferred improved performance (0.83, 95% CI: 0.78-0.88), with a simplified model showing similar performance (0.80, 95% CI: 0.74-0.86). The biomarker-enhanced and simplified prediction models achieved a C-statistic of 0.82 (95% CI: 0.71-0.93) and 0.74 (95% CI: 0.64-0.83) for the prediction of 5-year cardiovascular death., Conclusion: Biomarker-enhanced risk prediction strategies allow the identification of cancer patients at high risk of MACE and cardiovascular death. While external validation studies are ongoing, this first-of-its-kind risk score may provide the basis for personalized cardiovascular risk assessment across cancer entities., Competing Interests: Declaration of competing interests S.K. has received funding from the Jubiläumsstiftung SwissLife, the Lindenhof Foundation, the Novartis Foundation for Medical-Biological Research, the Swiss Heart Foundation, the Swiss Society of Cardiology, and the Theodor-Ida-Herzog-Egli Foundation, and materials and equipment from Roche Diagnostics. He has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and the PAM Theragnostics GmbH. L.L. is a co-inventor on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies that specifically bind IL-1α to reduce various sequelae of ischemia–reperfusion injury to the central nervous system. He further reports speaker fees from Daiichi Sankyo outside the submitted work. Moreover, he is counselor of the European Society for Clinical Investigation and has received fundings from the Novartis Foundation for Medical-Biological Research, the Swiss Heart Foundation, and the Italian Ministry of Health. T.M.S. declares funding from the Lindenhof Foundation. F.A.W. is supported by a grant of the Lindenhof Foundation (through S.K., T.F.L, and T.M.S.) and the Foundation for Cardiovascular Research—Zurich Heart House. He has received funding from the Fonds zur Förderung des akademischen Nachwuchses of the University of Zurich, the European Society of Cardiology, 4TEEN4 Pharmaceuticals GmbH, PAM Theragnostics GmbH, and Sphingotec GmbH outside the submitted work. Outside this work, I.P. reports honoraria for lectures from Bayer, BMS/Pfizer, and Sanofi and participation in advisory boards from Bayer and BMS/Pfizer. Outside this work, T.F.L. declares research and educational grants to the institution from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Menarini Foundation, Novartis, Novo Nordisk, Roche Diagnostics, Sanofi, and Vifor and honoraria from Amgen, Dacadoo, Daiichi Sankyo, Menarini Foundation, Novartis, Novo Nordisk, Philips, and Pfizer. He holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. C.A. reports honoraria for lectures from Bayer, Daiichi Sankyo, BMS/Pfizer, and Sanofi and participation in advisory boards from Bayer, Boehringer Ingelheim, Daiichi Sankyo, and BMS/Pfizer. F.Moik reports honoraria for lectures from BMS and MSD and participation in advisory boards from BMS. All other authors have no competing interests to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aims: Obesity and type 2 diabetes (T2D) are major risk factors for cardiovascular (CV) diseases. Dysregulated pro-apoptotic ceramide synthesis reduces β-cell insulin secretion, thereby promoting hyperglycaemic states that may manifest as T2D. Pro-apoptotic ceramides modulate insulin sensitivity and glucose tolerance while being linked to poor CV outcomes. Sirtuin-1 (SIRT1) is a NAD + -dependent deacetylase that protects against pancreatic β-cell dysfunction; however, systemic levels are decreased in obese-T2D mice and may promote pro-apoptotic ceramide synthesis and hyperglycaemia. Herein, we aimed to assess the effects of restoring circulating SIRT1 levels to prevent metabolic imbalance in obese and diabetic mice., Methods and Results: Circulating SIRT1 levels were reduced in obese-diabetic mice (db/db) as compared to age-matched non-diabetic db/+ controls. Restoration of SIRT1 plasma levels with recombinant murine SIRT1 for 4 weeks prevented body weight gain and improved glucose tolerance, insulin sensitivity, and vascular function in mice models of obesity and T2D. Untargeted lipidomics revealed that SIRT1 restored insulin secretory function of β-cells by reducing synthesis and accumulation of pro-apoptotic ceramides. Molecular mechanisms involved direct binding to and deacetylation of Toll-like receptor 4 (TLR4) by SIRT1 in β-cells, thereby decreasing the rate-limiting enzymes of sphingolipid synthesis SPTLC1/2 via AKT/NF-κB. Among patients with T2D, those with high baseline plasma levels of SIRT1 prior to metabolic surgery displayed restored β-cell function (HOMA2-β) and were more likely to have T2D remission during follow-up., Conclusion: Acetylation of TLR4 promotes β-cell dysfunction via ceramide synthesis in T2D, which is blunted by systemic SIRT1 replenishment. Hence, restoration of systemic SIRT1 may provide a novel therapeutic strategy to counteract toxic ceramide synthesis and mitigate CV complications of T2D., Competing Interests: Conflict of interest: There are no conflicts of interest related to this project except a partial support by Amgen, Inc., USA (to S.V.). G.G.C. and L.L. are coinventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies that specifically bind IL-1α to reduce various sequelae of ischaemia–reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida Solutions Limited. T.F.L. declares institutional educational and research grants outside this work from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis and Vifor, consulting fees from Daichi-Sankyo, Philipps, Pfizer, and Ineeo Inc and holds leadership positions at the European Society of Cardiology, the Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. S.K. declares research grants to the institution by the Jubiläumsstiftung SwissLife, the Lindenhof Foundation, the Novartis Foundation for Medical–Biological Research, the Swiss Heart Foundation, the Swiss Society of Cardiology, and the Theodor-Ida-Herzog-Egli Foundation and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, the Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and the PAM Theragnostics GmbH., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Competing Interests: Declaration of competing interest LL and GGC are coinventors on the International Patent (WO/2020/226993) filed in April 2020 and relating to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia–reperfusion injury to the central nervous system. The other authors report no conflict of interest.

Background: Inflammatory processes can trigger acute coronary syndromes (ACS) which may increase core body temperature (BT), a widely available low-cost marker of systemic inflammation. Herein, we aimed to delineate baseline characteristics of ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation ACS (NSTE-ACS) patients stratified by initial BT and to assess its predictive utility towards major adverse cardiovascular events (MACE) after the index ACS., Methods: From 2012 until 2017, a total of 1044 ACS patients, 517 with STEMI and 527 with NSTE-ACS, were prospectively recruited at the University Hospital Zurich. BT was measured by digital tympanic thermometer along with high-sensitivity C-reactive protein (hs-CRP) and cardiac troponin-T (hs-cTnT) levels prior to coronary angiography. Patients were stratified according to initial BT and uni- and multivariable regression models were fit to assess associations of BT with future MACE risk., Results: Among patients with STEMI, BT was not predictive of 1-year MACE, but a U-shaped relationship between BT and MACE risk was noted in those with NSTE-ACS (p = .029), translating into a 2.4-fold (HR, 2.44, 95% CI, 1.16-5.16) increased 1-year MACE risk in those with BT >36.8°C (reference: 36.6-36.8°C). Results remained robust in multivariable-adjusted analyses accounting for sex, age, diabetes, renal function and hs-cTnT. However, when introducing hs-CRP, the BT-MACE association did not prevail., Conclusions: In prospectively recruited patients with ACS, initial BT shows a U-shaped relationship with 1-year MACE risk among those with NSTE-ACS, but not in those with STEMI. BT is a broadly available low-cost marker to identify ACS patients with high inflammatory burden, at high risk for recurrent ischaemic events, and thus potentially suitable for an anti-inflammatory intervention., Registration: ClinicalTrials.gov Identifier: NCT01000701., (© 2024 The Author(s). European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Background and Aims: Circulating proenkephalin (PENK) is a stable endogenous polypeptide with fast response to glomerular dysfunction and tubular damage. This study examined the predictive value of PENK for renal outcomes and mortality in patients with acute coronary syndromes (ACS)., Methods: Proenkephalin was measured in plasma in a prospective multicentre ACS cohort from Switzerland (n=4787) and in validation cohorts from the UK (n=1141), Czechia (n=927), and Germany (n=220). A biomarker-enhanced risk score (KID-ACS score) for simultaneous prediction of in-hospital acute kidney injury (AKI) and 30-day mortality was derived and externally validated., Results: On multivariable adjustment for established risk factors, circulating PENK remained associated with in-hospital AKI (per log2 increase: adjusted odds ratio [OR] 1.53, 95% confidence interval [CI] 1.13-2.09, P=0.007) and 30-day mortality (adjusted hazard ratio [HR] 2.73, 95% CI 1.85-4.02, P<0.001). The KID-ACS score integrates PENK and showed an area under the receiver operating characteristic curve (AUC) of 0.72 (95% CI 0.68-0.76) for in-hospital AKI, and of 0.91 (95% CI 0.87-0.95) for 30-day mortality in the derivation cohort. Upon external validation, KID-ACS achieved similarly high performance for in-hospital AKI (Zurich: AUC 0.73, 95% CI 0.70-0.77; Czechia: AUC 0.75, 95% CI 0.68-0.81; Germany: AUC 0.71, 95% CI 0.55-0.87) and 30-day mortality (UK: AUC 0.87, 95% CI 0.83-0.91; Czechia: AUC 0.91, 95% CI 0.87-0.94; Germany: AUC 0.96, 95% CI 0.92-1.00) outperforming the CA-AKI score and the GRACE 2.0 score, respectively., Conclusions: Circulating PENK offers incremental value for predicting in-hospital AKI and mortality in ACS. The simple 6-item KID-ACS risk score integrates PENK and provides a novel tool for simultaneous assessment of renal and mortality risk in patients with ACS., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Data on glycoprotein IIb/IIIa inhibitor (GPI) use in real-world acute coronary syndrome (ACS) patients following the introduction of potent P2Y12 inhibitors and newer-generation stents are scant. Here, we aimed to assess the utilization, effectiveness, and safety of GPI in a large prospective multicentre cohort of contemporary ACS patients., Methods and Results: SPUM-ACS prospectively recruited patients presenting with ACS between 2009 and 2017. The primary endpoint of the present study was major adverse cardiovascular events (MACE), a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke at 1 year. Secondary endpoints were defined as any bleeding events, Bleeding Academic Research Consortium (BARC) 3-5 bleeding, and net adverse cardiovascular events (NACE). A total of 4395 ACS patients were included in the analysis. GPI-treated patients had more total coronary artery occlusion (56% vs. 35%, P < 0.001) and thrombus (60% vs. 35%, P < 0.001) at angiography. Among the propensity score-matched (PSM) population (1992 patients equally split into two groups), GPI-treated patients showed lower risk of MACE [PSM adjusted hazard ratio (HR) 0.70, 95% CI 0.49-0.99], but a higher risk of any (PSM adjusted HR 1.46, 95% CI 1.06-1.99) and major bleedings (PSM adjusted HR 1.73, 95% CI 1.09-2.76), resulting in a neutral effect on NACE (PSM adjusted HR 0.87, 95% CI 0.65-1.17). These results remained consistent across all subgroups., Conclusions: In patients with ACS undergoing percutaneous coronary intervention and receiving potent P2Y12 inhibitors, we observed a reduced risk of MACE and an increased risk of major bleedings at 1 year in patients treated with GPI. Although the routine use of GPI is currently not recommended, they might be considered in selected patients following a personalized balancing between ischaemic and bleeding risks., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: High-intensity focused ultrasound (HIFU) emerged as a novel approach for the treatment of localized prostate cancer (PCa). However, prospective studies on HIFU-related outcomes and predictors of treatment failure (TF) remain scarce., Materials and Methods: We conducted a multinational prospective cohort study among patients undergoing HIFU therapy for localized, low- to intermediate-risk PCa. Follow-up data on serial prostate specific antigen (PSA), multi-parametric magnetic resonance imaging (mpMRI), targeted/systematic biopsies, adverse events and functional outcomes were collected. The primary endpoint was TF, defined as histologically confirmed PCa requiring whole-gland salvage treatment. Uni- and multi-variable adjusted hazard ratios (HRs) were calculated using Cox proportional hazard regression models., Results: At baseline, mean (standard deviation) age was 64.14 (7.19) years, with the majority of patients showing T-stage 1 (73.9%) and International Society of Urological Pathology grading system Grade 2 (58.8%). PSA nadir (median, 1.70 ng/mL) was reached after 6 months. Of all patients recruited, 16% had clinically significant PCa, as confirmed by biopsy, of which 13.4% had TF. Notably, T-stage and number of positive cores at initial biopsy were independent predictors of TF during follow-up (HR [95% CI] 1.27 [1.02-1.59] and 5.02 [1.80-14.03], respectively). Adverse events were minimal (17% and 8% early and late adverse events, respectively), with stable or improved functional outcomes in the majority of patients., Conclusions: This interim analysis of a multinational study on HIFU therapy for the management of low-to-intermediate-risk PCa reveals good functional outcomes, minimal adverse events and low incidence of TF over the short-term. Data on long-term outcomes, specifically as it relates to oncological outcomes, are awaited eagerly., (© 2024 The Authors. European Journal of Clinical Investigation published by John Wiley & Sons Ltd on behalf of Stichting European Society for Clinical Investigation Journal Foundation.)

Nogo-A is a transmembrane protein with multiple functions in the central nervous system (CNS), including restriction of neurite growth and synaptic plasticity. Thus far, Nogo-A has been predominantly considered a cell contact-dependent ligand signaling via cell surface receptors. Here, we show that Nogo-A can be secreted by cultured cells of neuronal and glial origin in association with extracellular vesicles (EVs). Neuron- and oligodendrocyte-derived Nogo-A containing EVs inhibited fibroblast spreading, and this effect was partially reversed by Nogo-A receptor S1PR2 blockage. EVs purified from HEK cells only inhibited fibroblast spreading upon Nogo-A over-expression. Nogo-A-containing EVs were found in vivo in the blood of healthy mice and rats, as well as in human plasma. Blood Nogo-A concentrations were elevated after acute stroke lesions in mice and rats. Nogo-A active peptides decreased barrier integrity in an in vitro blood-brain barrier model. Stroked mice showed increased dye permeability in peripheral organs when tested 2 weeks after injury. In the Miles assay, an in vivo test to assess leakage of the skin vasculature, a Nogo-A active peptide increased dye permeability. These findings suggest that blood borne, possibly EV-associated Nogo-A could exert long-range regulatory actions on vascular permeability.

An increasing number of individuals are at high risk of type 2 diabetes (T2D) and its cardiovascular complications, including heart failure (HF), chronic kidney disease (CKD), and eventually premature death. The sodium-glucose co-transporter-2 (SGLT2) protein sits in the proximal tubule of human nephrons to regulate glucose reabsorption and its inhibition by gliflozins represents the cornerstone of contemporary T2D and HF management. Herein, we aim to provide an updated overview of the pleiotropy of gliflozins, provide mechanistic insights and delineate related cardiovascular (CV) benefits. By discussing contemporary evidence obtained in preclinical models and landmark randomized controlled trials, we move from bench to bedside across the broad spectrum of cardio- and cerebrovascular diseases. With landmark randomized controlled trials confirming a reduction in major adverse CV events (MACE; composite endpoint of CV death, non-fatal myocardial infarction, and non-fatal stroke), SGLT2 inhibitors strongly mitigate the risk for heart failure hospitalization in diabetics and non-diabetics alike while conferring renoprotection in specific patient populations. Along four major pathophysiological axes (i.e. at systemic, vascular, cardiac, and renal levels), we provide insights into the key mechanisms that may underlie their beneficial effects, including gliflozins' role in the modulation of inflammation, oxidative stress, cellular energy metabolism, and housekeeping mechanisms. We also discuss how this drug class controls hyperglycaemia, ketogenesis, natriuresis, and hyperuricaemia, collectively contributing to their pleiotropic effects. Finally, evolving data in the setting of cerebrovascular diseases and arrhythmias are presented and potential implications for future research and clinical practice are comprehensively reviewed., Competing Interests: Conflict of interest: T.F.L. has no conflicts of interest related to this work. T.F.L. has received institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Novo Nordisk, Sanofi and Vifor and consulting fees from Daiichi Sankyo, and Novo Nordisk. T.F.L. has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Menarini Foundation, Daichi Sankyo and Abbott India. T.F.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. L.L. and G.G.C. are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. L.L. reports speaker fees outside of this work from Daiichi-Sankyo. G.G.C. is a consultant to Sovida Solutions Limited. S.K. declares research grants to the institution from the Jubiläumsstiftung SwissLife, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Heart Foundation, the Swiss Society of Cardiology, and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and PAM Theragnostics GmbH. All other authors report no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Adipokines are key mediators of inflammation in metabolic syndrome perpetuating the effect of excess nutrient intake by setting a self-maintaining vicious circle. Here, we assess levels of adiponectin and leptin in a cohort of individuals with MetS undergoing dietary and behavioral counselling. Specifically, we investigate their role as predictors of metabolic syndrome remission after 1 year., Methods: Patients with MetS (n = 127) received behavioral and dietary recommendations and were followed-up for 1 year. Serum was available for 108 individuals, levels of adiponectin and leptin were tested at baseline, at 6 months (t1) and after 1 year (t2). Adiponectin/leptin (A/L) ratio was also calculated and tested for predictive ability., Result: At the end of the follow-up period, 59 patients did not show enough criteria to define MetS anymore. When considered alone, adiponectin and leptin levels did not show difference over follow-up. Their ratio instead was significantly reduced at t1 and t2 with respect to baseline. Remitters also showed lowers level of leptin and A/L ratio as compared to non-remitters at t1. At this timepoint, A/L ratio independently predicted MetS remission at 1 year [OR 9.082 95%CI (1.394-59.160), p = 0.021]. Bootstrap resampling analysis internally validated our findings., Conclusions: Preliminary results from our pilot study suggest that MetS remission after counselling associates with changes in adipokine balance. A/L ratio decreases overtime and its value at 6 months can independently predict MetS remission., Competing Interests: Declaration of competing interest LL is coinventors on the International Patent (WO/2020/226993) filed in April 2020 and relating to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia–reperfusion injury to the central nervous system. LL has received speaker fees outside of this work from Daichi-Sankyo. AB received honoraria from Effetti s.r.l. (Milan, Italy) to collaborate on the medical website www.inflammology.org, outside the present work. S.K. declares research grants to the institution from the Jubiläumsstiftung SwissLife, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Heart Foundation, the Swiss Society of Cardiology, and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and PAM Theragnostics GmbH. The other authors report no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Aims: The heart rejuvenating effects of circulating growth differentiation factor 11 (GDF11), a transforming growth factor-β superfamily member that shares 90% homology with myostatin (MSTN), remains controversial. Here, we aimed to probe the role of GDF11 in acute myocardial infarction (MI), a frequent cause of heart failure and premature death during ageing., Methods and Results: In contrast to endogenous Mstn, myocardial Gdf11 declined during the course of ageing and was particularly reduced following ischaemia/reperfusion (I/R) injury, suggesting a therapeutic potential of GDF11 signalling in MI. Unexpectedly, boosting systemic Gdf11 by recombinant GDF11 delivery (0.1 mg/kg body weight over 30 days) prior to myocardial I/R augmented myocardial infarct size in C57BL/6 mice irrespective of their age, predominantly by accelerating pro-apoptotic signalling. While intrinsic cardioprotective signalling pathways remained unaffected by high circulating GDF11, targeted transcriptomics and immunomapping studies focusing on GDF11-associated downstream targets revealed attenuated Nkx2-5 expression confined to CD105-expressing cells, with pro-apoptotic activity, as assessed by caspase-3 levels, being particularly pronounced in adjacent cells, suggesting an indirect effect. By harnessing a highly specific and validated liquid chromatography-tandem mass spectrometry-based assay, we show that in prospectively recruited patients with MI circulating GDF11 but not MSTN levels incline with age. Moreover, GDF11 levels were particularly elevated in those at high risk for adverse outcomes following the acute event, with circulating GDF11 emerging as an independent predictor of myocardial infarct size, as estimated by standardized peak creatine kinase-MB levels., Conclusion: Our data challenge the initially reported heart rejuvenating effects of circulating GDF11 and suggest that high levels of systemic GDF11 exacerbate myocardial injury in mice and humans alike. Persistently high GDF11 levels during ageing may contribute to the age-dependent loss of cardioprotective mechanisms and thus poor outcomes of elderly patients following acute MI., Competing Interests: Conflict of interest: S.K. declares research grants from the Swiss Heart Foundation, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Society of Cardiology, the Jubiläumsstiftung SwissLife and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. Further, he has received travel support from the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and PAM Theragnostics GmbH. T.F.L. has no conflicts of interest related to this manuscript but has received institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor and consulting fees from Daiichi Sankyo, Ineeo Inc., Philips, and Pfizer outside the submitted work. T.F.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. G.G.C. and L.L. are co-inventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of I/R injury to the central nervous system. G.G.C. is a consultant to Sovida Solutions Limited. L.L. reports speaker fees outside of this work from Daiichi Sankyo. F.A.W. received travel support by 4TEEN4 Pharmaceuticals GmbH, PAM Theragnostics GmbH, and Sphingotec GmbH. L.R. received research grants by Abbott, Biotronik, Boston Scientific, HeartFlow, Infraredx, Sanofi, and Regeneron and reports consultation/advisory board fees by Abbott, AstraZeneca, Amgen, Canon, Novo Nordisk, Medtronic, and Occlutech. C.M.M. has received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen, Novartis, Novo Nordisk, and MSD including speaker or consultant fees., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Enhancing SIRT1 activity exerts beneficial cardiovascular effects. In diabetes, plasma SIRT1 levels are reduced. We aimed to investigate the therapeutic potential of chronic recombinant murine SIRT1 (rmSIRT1) supplementation to alleviate endothelial and vascular dysfunction in diabetic mice (db/db)., Methods and Results: Left internal mammary arteries obtained from patients undergoing coronary artery bypass grafting with or without a diagnosis of diabetes were assayed for SIRT1 protein levels. Twelve-week-old male db/db mice and db/+ controls were treated with vehicle or rmSIRT1 intraperitoneally for 4 weeks, after which carotid artery pulse wave velocity (PWV) and energy expenditure/activity were assessed by ultrasound and metabolic cages, respectively. Aorta, carotid, and mesenteric arteries were isolated to determine endothelial and vascular function using the myograph system.Arteries obtained from diabetic patients had significantly lower levels of SIRT1 relative to non-diabetics. In line, aortic SIRT1 levels were reduced in db/db mice compared to db/+ mice, while rmSIRT1 supplementation restored SIRT1 levels. Mice receiving rmSIRT1 supplementation displayed increased physical activity and improved vascular compliance as reflected by reduced PWV and attenuated collagen deposition. Aorta of rmSIRT1-treated mice exhibited increased endothelial nitric oxide (eNOS) activity, while endothelium-dependent contractions of their carotid arteries were significantly decreased, with mesenteric resistance arteries showing preserved hyperpolarization. Ex vivo incubation with reactive oxygen species (ROS) scavenger Tiron and NADPH oxidase inhibitor apocynin revealed that rmSIRT1 leads to preserved vascular function by suppressing NADPH oxidase (NOX)-related ROS synthesis. Chronic rmSIRT1 treatment resulted in reduced expression of both NOX1 and NOX4, in line with a reduction in aortic protein carbonylation and plasma nitrotyrosine levels., Conclusions: In diabetic conditions, arterial SIRT1 levels are significantly reduced. Chronic rmSIRT1 supplementation improves endothelial function and vascular compliance by enhancing eNOS activity and suppressing NOX-related oxidative stress. Thus, SIRT1 supplementation may represent novel therapeutic strategy to prevent diabetic vascular disease., Competing Interests: Conflict of interest: K.Y., S.V., A.A., T.L.-B., M.O.S., X.W., L.G., and A.X. have no conflicts of interest to report. S.K. has received funding from the Jubiläumsstiftung SwissLife, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, the Swiss Heart Foundation, the Swiss Society of Cardiology, and the Theodor-Ida-Herzog-Egli Foundation, and materials and equipment from Roche Diagnostics outside the submitted work. Outside the submitted work, he has also been supported by the European Atherosclerosis Society, the European Society of Cardiology, the European Society of Clinical Investigation, Sphingotec GmbH, the 4TEEN4 Pharmaceuticals GmbH, and the PAM Theragnostics GmbH. T.F.L. has no conflicts related to this manuscript, but outside this work has received education and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi Sankyo, Novartis, Sanofi, Servier, and Vifor. G.G.C. is a coinventor on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies that specifically bind IL-1α to reduce various sequelae of ischaemia-reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida Solutions Limited., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background and Aims: Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II which disturbs peripheral blood pressure regulation and compromises left ventricular function. This study examined the relationship of circulating DPP3 (cDPP3) with cardiogenic shock (CS) and mortality in patients presenting with acute coronary syndromes (ACS)., Methods: Plasma cDPP3 levels were assessed at baseline and 12-24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787)., Results: Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score [per log-2 increase, hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.05-1.82, P = .021]. High cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, 95% CI 1.36-2.58, P < .001) and at one year (HR 1.61, 95% CI 1.28-2.02, P < .001) after adjustment for established risk factors and the GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12-24 h were associated with 13.4-fold increased 30-day mortality risk (HR 13.42, 95% CI 4.86-37.09, P < .001) and 5.8-fold increased 1-year mortality risk (HR 5.79, 95% CI 2.70-12.42, P < .001). Results were consistent across various patient subgroups., Conclusions: This study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Importance: The Global Registry of Acute Coronary Events (GRACE) risk score, a guideline-recommended risk stratification tool for patients presenting with acute coronary syndromes (ACS), does not consider the extent of myocardial injury., Objective: To assess the incremental predictive value of a modified GRACE score incorporating high-sensitivity cardiac troponin (hs-cTn) T at presentation, a surrogate of the extent of myocardial injury., Design, Setting, and Participants: This retrospectively designed longitudinal cohort study examined 3 independent cohorts of 9803 patients with ACS enrolled from September 2009 to December 2017; 2 ACS derivation cohorts (Heidelberg ACS cohort and Newcastle STEMI cohort) and an ACS validation cohort (SPUM-ACS study). The Heidelberg ACS cohort included 2535 and the SPUM-ACS study 4288 consecutive patients presenting with a working diagnosis of ACS. The Newcastle STEMI cohort included 2980 consecutive patients with ST-elevation myocardial infarction treated with primary percutaneous coronary intervention. Data were analyzed from March to June 2023., Exposures: In-hospital, 30-day, and 1-year mortality risk estimates derived from an updated risk score that incorporates continuous hs-cTn T at presentation (modified GRACE)., Main Outcomes and Measures: The predictive value of continuous hs-cTn T and modified GRACE risk score compared with the original GRACE risk score. Study end points were all-cause mortality during hospitalization and at 30 days and 1 year after the index event., Results: Of 9450 included patients, 7313 (77.4%) were male, and the mean (SD) age at presentation was 64.2 (12.6) years. Using continuous rather than binary hs-cTn T conferred improved discrimination and reclassification compared with the original GRACE score (in-hospital mortality: area under the receiver operating characteristic curve [AUC], 0.835 vs 0.741; continuous net reclassification improvement [NRI], 0.208; 30-day mortality: AUC, 0.828 vs 0.740; NRI, 0.312; 1-year mortality: AUC, 0.785 vs 0.778; NRI, 0.078) in the derivation cohort. These findings were confirmed in the validation cohort. In the pooled population of 9450 patients, modified GRACE risk score showed superior performance compared with the original GRACE risk score in terms of reclassification and discrimination for in-hospital mortality end point (AUC, 0.878 vs 0.780; NRI, 0.097), 30-day mortality end point (AUC, 0.858 vs 0.771; NRI, 0.08), and 1-year mortality end point (AUC, 0.813 vs 0.797; NRI, 0.056)., Conclusions and Relevance: In this study, using continuous rather than binary hs-cTn T at presentation, a proxy of the extent of myocardial injury, in the GRACE risk score improved the mortality risk prediction in patients with ACS.

Background: Patients with cancer are at increased risk of venous thromboembolism (VTE) and arterial thromboembolic/thrombotic events (ATEs). Growth differentiation factor-15 (GDF-15) improves cardiovascular risk assessment, but its predictive utility in patients with cancer remains undefined., Objectives: To investigate the association of GDF-15 with the risks of VTE, ATE, and mortality in patients with cancer and its predictive utility alongside established models., Methods: The Vienna Cancer and Thrombosis Study (CATS)-a prospective, observational cohort study of patients with newly diagnosed or recurrent cancer-which was followed for 2 years, served as the study framework. Serum GDF-15 levels at study inclusion were measured, and any association with VTE, ATE, and death was determined using competing risk (VTE/ATE) or Cox regression (death) modeling. The added value of GDF-15 to established VTE risk prediction models was assessed using the Khorana and Vienna CATScore., Results: Among 1531 included patients with cancer (median age, 62 years; 53% men), median GDF-15 levels were 1004 ng/L (IQR, 654-1750). Increasing levels of GDF-15 were associated with the increased risks of VTE, ATE, and all-cause death ([subdistribution] hazard ratio per doubling, 1.16 [95% CI, 1.03-1.32], 1.30 [95% CI, 1.11-1.53], and 1.57 [95% CI, 1.46-1.69], respectively). After adjustment for clinically relevant covariates, the association only prevailed for all-cause death (hazard ratio, 1.21; 95% CI, 1.10-1.33) and GDF-15 did not improve the performance of the Khorana or Vienna CATScore., Conclusion: GDF-15 is strongly associated with survival in patients with cancer, independent of the established risk factors. While an association with ATE and VTE was identified in univariable analysis, GDF-15 was not independently associated with these outcomes and failed to improve established VTE prediction models., Competing Interests: Declaration of competing interests S.K. received funding from the Swiss Heart Foundation, the Lindenhof Foundation, the Novartis Foundation for Medical-biological Research, and the Theodor-Ida-Herzog-Egli Foundation outside the submitted work. M.P. has received honoraria for lectures, consultation, or advisory board participation from the following for-profit companies: Bayer, Bristol-Myers Squibb, Novartis, Gerson Lehrman Group, CMC Contrast, GlaxoSmithKline, Mundipharma, Roche, BMJ Journals, MedMedia, Astra Zeneca, AbbVie, Lilly, Medahead, Daiichi Sankyo, Sanofi, Merck Sharp & Dome, Tocagen, Adastra, Gan & Lee Pharmaceuticals, and Servier. T.F.L. has received institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor and consulting fees from Daiichi Sankyo, Ineeo Inc, Philipps, and Pfizer outside the submitted work. T.F.L. holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. The remaining authors S.N., F.M., C.E., A.v.E., I.P., and C.A. have no competing interests to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Objectives: Mindfulness-based interventions (including self-compassion interventions) are effective in improving stress management at psychological and physical levels. Mindful Self-Compassion (MSC) is a newly developed program particularly aimed at increasing self-compassion. The main objective of this study was to determine whether the psychophysiological stress response during a social-evaluative speaking task differs in inpatients participating in the MSC or the Progressive Muscle Relaxation (PMR) program at the end of their 6-week psychiatric rehabilitation stay (i.e., post-test only design)., Method: Data from 50 inpatients (25 MSC, 25 PMR, 35 female) aged 19 to 76 years ( M  = 47.22, SD  = 12.44) were analyzed in terms of psychophysiological stress response. For this purpose, heart rate variability, heart rate, and blood pressure were assessed together with several psychometric variables: positive and negative affect (PANAS), subjective stress perception (Visual Analog Scale), self-compassion (Self-Compassion Scale), cognitive reappraisal and suppression (Emotion Regulation Questionnaire), psychological distress (Brief Symptom Inventory-18), and appraisal and rumination (selected items)., Results: After correction for alpha inflation no differences in the psychophysiological stress response and psychometric parameters between the MSC and PMR group were found., Discussion: In general, our results indicate that MSC is not superior to PMR training. However, more research with clinical randomized controlled trials investigating larger samples are needed to further affirm these initial findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Andorfer, Kraler, Kaufmann, Pollheimer, Spah, Fuchshuber, Rominger, Traunmüller, Schwerdtfeger and Unterrainer.)

Aims: Outcomes after acute coronary syndromes (ACS) are determined by baseline risk profiles, including initial systolic blood pressure (sBP) levels. Herein, we aimed to characterize ACS patients stratified by initial sBP levels and study their relation to inflammation, myocardial injury and post-ACS outcomes., Methods and Results: We analysed 4724 prospectively recruited ACS patients according to invasively assessed sBP (<100, 100-139, and ≥140 mmHg) at admission. Biomarkers of systemic inflammation [high-sensitivity C-reactive protein (hs-CRP)] and myocardial injury [high-sensitivity cardiac troponin T (hs-cTnT)] were measured centrally. Major adverse cardiovascular events (MACE; composite measure of non-fatal myocardial infarction, non-fatal stroke, and cardiovascular death) were externally adjudicated. Leukocyte counts, hs-CRP, hs-cTnT, and creatine kinase (CK) levels decreased from low to high sBP strata (ptrend < 0.001). Patients with sBP < 100 mmHg developed more often cardiogenic shock (CS; P < 0.001), and had a 1.7-fold increased multivariable-adjusted MACE risk at 30 days (HR 1.68, 95% CI 1.05-2.69, P = 0.031) which did not persist at one year (HR 1.38, 95% CI 0.92-2.05, P = 0.117). Those with sBP < 100 mmHg and CS showed a higher leukocyte count (P < 0.001), an increased neutrophil-to-lymphocyte-ratio (P = 0.031), and higher hs-cTnT and CK levels relative to those without CS (P < 0.001 and P = 0.002, respectively), whereas hs-CRP levels did not differ. Patients who developed CS had a 3.6- and 2.9-fold increased MACE risk at 30 days (HR 3.58, 95% CI 1.77-7.24, P < 0.001) and at one year (HR 2.94 95% CI, 1.57-5.53, P < 0.001), which was intriguingely attenuated after controlling for distinct inflammatory profiles., Conclusion: In patients with ACS, proxies of systemic inflammation and myocardial injury are inversely associated with initial sBP levels, with highest biomarker levels observed in those <100 mmHg. If linked to high levels of cellular inflammation, these patients are prone to develop CS and are at high MACE and mortality risk., Competing Interests: Conflicts of interest: Outside this work, T.F.L. has received educational and research grants from Abbott, Ablative Solutions, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, Sanofi, Servier, and Vifor. None of the sponsors had any role in the conceptualization of the study, data collection, data analysis, data interpretation, or writing of the report. This work was further supported by the Foundation for Cardiovascular Research - Zurich Heart House (to S.K., F.A.W., and T.F.L.), the Swiss Heart Foundation (to T.F.L. and S.K.), the Lindenhofstiftung (to T.F.L. and S.K.), and the Theodor Ida Herzog-Egli Stiftung (to S.K.). S.K. has further received funding from the Novartis Foundation for Medical-biological Research and equipment and materials from Roche Diagnostics outside the submitted work. L.R. has received funding from Abbott, Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron, and declares consulting fees from Abbott, Amgen, AstraZeneca, Canon, Medtronic, NovoNordisk, Occlutech, Sanofi, and Vifor, payment or honoraria from Abbott and Occlutech, and travel support from AstraZeneca. A.v.E. received speaker and/or consultant fees from Amgen, MSD, and Sanofi-Aventis. M.R. declares institutional research grants from Terumo, Biotronik, Medtronic, Cordis/Cardinal Health, and Boston Scientific, outside the submitted work. The other authors do not report no conflicts of interests related to this manuscript., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Patients with acute coronary syndromes (ACS) remain at risk of cardiovascular disease (CVD) recurrences. Peripheral artery disease (PAD) may identify a very high risk (VHR) group who may derive greater benefit from intensified secondary prevention., Methods: Among ACS-patients enrolled in the prospective multi-center Special Program University Medicine (SPUM), we assessed the impact of PAD on major cardiovascular events (MACE: composite of myocardial infarction, stroke and all-cause death) and major bleeding. Multivariate analysis tested the relation of each significant variable with MACE, as well as biomarkers of inflammation and novel markers of atherogenesis., Results: Out of 4787 ACS patients, 6.0% (n = 285) had PAD. PAD-patients were older (p < 0.001), with established CVD and signs of increased persistent inflammation (hs-CRP; 23.6 ± 46.5 vs 10.4 ± 27.2 mg/l, p < 0.001 and sFlt-1; 1399.5 ± 1501.3 vs 1047.2 ± 1378.6 ng/l, p = 0.018). In-hospital-death (3.2% vs 1.4%, p = 0.022) and -MACE (5.6% vs 3.0%, p = 0.017) were higher in PAD-patients. MACE at 1 year (18.6% vs 7.9%,p < 0.001) remained increased even after adjustment for confounders (Adj. HR 1.53, 95% CI: 1.14-2.08, p = 0.005). Major bleeding did not differ between groups (Adj. HR 1.18; 95% CI 0.71-1.97, p = 0.512). Although PAD predicted MACE, PAD-patients were prescribed less frequently for secondary prevention at discharge., Conclusions: In this real-world ACS patient cohort, concomitant PAD is a marker of VHR and is associated with increased and persistent inflammation, higher risk for MACE without an increased risk of major bleeding. Therefore, a history of PAD may be useful to identify those ACS patients at VHR who require more aggressive secondary prevention., Competing Interests: Declaration of Competing Interest LR received research grants to the institution by Abbott, Biotronik, Heartflow, Sanofi, Regeneron and speaker/consultation fees by Abbott, Amgen, AstraZeneca, Canon, Novo Nordisk, Medtronic, Sanofi, Occlutech, Vifor. TFL received outside this project research and educational grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Sanofi, Servier and Vifor and honoraria from Amgen, Daichi-Sankyo, Novartis, Sanofi all Switzerland, DalCor International, Inbeeo-NonoNordisk, India, Pfizer UK, Philipps, Europe. All other authors have no conflicts of interest., (Copyright © 2023. Published by Elsevier B.V.)

Background and Aims: Low-density lipoprotein (LDL)-cholesterol (LDL-C) promotes atherosclerotic cardiovascular disease (ASCVD), with changes in LDL electronegativity modulating its pro-atherogenic/pro-thrombotic effects. Whether such alterations associate with adverse outcomes in patients with acute coronary syndromes (ACS), a patient population at particularly high cardiovascular risk, remains unknown., Methods: This is a case-cohort study using data from a subset of 2619 ACS patients prospectively recruited at four university hospitals in Switzerland. Isolated LDL was chromatographically separated into LDL particles with increasing electronegativity (L1-L5), with the L1-L5 ratio serving as a proxy of overall LDL electronegativity. Untargeted lipidomics revealed lipid species enriched in L1 (least) vs. L5 (most electronegative subfraction). Patients were followed at 30 days and 1 year. The mortality endpoint was reviewed by an independent clinical endpoint adjudication committee. Multivariable-adjusted hazard ratios (aHR) were calculated using weighted Cox regression models., Results: Changes in LDL electronegativity were associated with all-cause mortality at 30 days (aHR, 2.13, 95% CI, 1.07-4.23 per 1 SD increment in L1/L5; p=.03) and 1 year (1.84, 1.03-3.29; p=.04), with a notable association with cardiovascular mortality (2.29; 1.21-4.35; p=.01; and 1.88; 1.08-3.28; p=.03). LDL electronegativity superseded several risk factors for the prediction of 1-year death, including LDL-C, and conferred improved discrimination when added to the updated GRACE score (area under the receiver operating characteristic curve 0.74 vs. 0.79, p=.03). Top 10 lipid species enriched in L1 vs. L5 were: cholesterol ester (CE) (18:2), CE (20:4), free fatty acid (FA) (20:4), phosphatidyl-choline (PC) (36:3), PC (34:2), PC (38:5), PC (36:4), PC (34:1), triacylglycerol (TG) (54:3), and PC (38:6) (all p < .001), with CE (18:2), CE (20:4), PC (36:3), PC (34:2), PC (38:5), PC (36:4), TG (54:3), and PC (38:6) independently associating with fatal events during 1-year of follow-up (all p < .05)., Conclusions: Reductions in LDL electronegativity are linked to alterations of the LDL lipidome, associate with all-cause and cardiovascular mortality beyond established risk factors, and represent a novel risk factor for adverse outcomes in patients with ACS. These associations warrant further validation in independent cohorts., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: SK also received funding from the Swiss Heart Foundation, the Novartis Foundation for Medical-biological Research, and the Theodor-Ida-Herzog-Egli Foundation, and equipment and materials from Roche Diagnostics outside the submitted work. LR received funding from Abbott, Biotronik, Boston Scientific, Heartflow, Sanofi, and Regeneron, and declares consulting fees from Abbott, Amgen, AstraZeneca, Canon, Medtronic, NovoNordisk, Occlutech, Sanofi, and Vifor, payment or honoraria from Abbott and Occlutech, and travel support from AstraZeneca. FM has received research grants to the institution from Amgen, AstraZeneca, Boston Scientific, Biotronik, Eli Lilly, Medtronic, MSD, and St. Jude Medical, including speaker and/or consultant fees. AvE received speaker and/or consultant fees from Amgen, MSD, and Sanofi-Aventis. CMM received research grants to the institution from Eli Lilly, AstraZeneca, Roche, Amgen and MSD including speaker or consultant fees. GGC and LL are co-inventors on the international patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischaemia–reperfusion injury to the central nervous system. GGC.is a consultant to Sovida Solutions Limited. LL reports speaker fees from Daiichi Sankyo outside the submitted work. Outside this work, TFL declares institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, Novartis, and Vifor, and consulting fees from Daiichi Sankyo, Ineeo Inc, Philipps, and Pfizer outside the submitted work. TFL holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. All other authors declare no competing interests., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Aims: Variants of the junctional cadherin 5 associated (JCAD) locus associate with acute coronary syndromes. JCAD promotes experimental atherosclerosis through the large tumor suppressor kinase 2 (LATS2)/Hippo pathway. This study investigates the role of JCAD in arterial thrombosis., Methods and Results: JCAD knockout (Jcad-/-) mice underwent photochemically induced endothelial injury to trigger arterial thrombosis. Primary human aortic endothelial cells (HAECs) treated with JCAD small interfering RNA (siJCAD), LATS2 small interfering RNA (siLATS2) or control siRNA (siSCR) were employed for in vitro assays. Plasma JCAD was measured in patients with chronic coronary syndrome or ST-elevation myocardial infarction (STEMI). Jcad-/- mice displayed reduced thrombogenicity as reflected by delayed time to carotid occlusion. Mechanisms include reduced activation of the coagulation cascade [reduced tissue factor (TF) expression and activity] and increased fibrinolysis [higher thrombus embolization episodes and D-dimer levels, reduced vascular plasminogen activator inhibitor (PAI)-1 expression]. In vitro, JCAD silencing inhibited TF and PAI-1 expression in HAECs. JCAD-silenced HAECs (siJCAD) displayed increased levels of LATS2 kinase. Yet, double JCAD and LATS2 silencing did not restore the control phenotype. si-JCAD HAECs showed increased levels of phosphoinositide 3-kinases (PI3K)/ proteinkinase B (Akt) activation, known to downregulate procoagulant expression. The PI3K/Akt pathway inhibitor-wortmannin-prevented the effect of JCAD silencing on TF and PAI-1, indicating a causative role. Also, co-immunoprecipitation unveiled a direct interaction between JCAD and Akt. Confirming in vitro findings, PI3K/Akt and P-yes-associated protein levels were higher in Jcad-/- animals. Lastly, as compared with chronic coronary syndrome, STEMI patients showed higher plasma JCAD, which notably correlated positively with both TF and PAI-1 levels., Conclusions: JCAD promotes arterial thrombosis by modulating coagulation and fibrinolysis. Herein, reported translational data suggest JCAD as a potential therapeutic target for atherothrombosis., Competing Interests: Conflict of interest: L.L. and G.G.C. are coinventors on the International Patent WO/2020/226993 filed in April 2020. The patent relates to the use of antibodies which specifically bind IL-1α to reduce various sequelae of ischemia-reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. T.F.L. has no conflicts related to this manuscript. Outside the work he received unrestricted research and education grants from Abbott, Amgen, Boehringer Ingelheim, Daichi-Sankyo, Novartis, Roche Diagnostics, Sanofi, Servier and Vifor. L.L. reports speaker fees outside of this work from Daichi-Sankyo. G.L. reports Consulting fees and Payment or honoraria for lectures: Novo Nordisk, Novartis, Sanofi, AstraZeneca, Boehringer, Bayer. F.C. reports speaker fees from Amgen, Astra Zeneca, Servier, BMS, other from GlyCardial Diagnostics, outside the submitted work. The other authors report no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aims: Low-grade inflammation couples dysmetabolic states to insulin resistance and atherosclerotic cardiovascular (CV) disease (ASCVD). Selective sodium-glucose co-transporter 2 (SGLT-2) inhibition by empagliflozin improves clinical outcomes in patients with ASCVD independently of its glucose lowering effects. Yet, its mechanism of action remains largely undetermined. Here, we aimed to test whether empagliflozin affects arterial thrombus formation in baseline (BSL) conditions or low-grade inflammatory states, a systemic milieu shared among patients with ASCVD., Methods and Results: Sixteen-week-old C57BL/6 mice were randomly assigned to acute administration of empagliflozin (25 mg/kg body weight) or vehicle, of which a subgroup was pre-treated biweekly over 4 weeks with super-low-dose lipopolysaccharide (LPS; 5 ng/kg body weight), before carotid thrombosis was induced by photochemical injury. The between-group difference in Doppler-flow probe detected time-to-occlusion remained within the predefined equivalence margin (Δ = |10.50|), irrespective of low-grade inflammation (95% confidence interval, -9.82 to 8.85 and -9.20 to 9.69), while glucose dropped by 1.64 and 4.84 mmoL/L, respectively. Ex vivo platelet aggregometry suggested similar activation status, corroborated by unchanged circulating platelet-factor 4 plasma levels. In concert, carotid PAI-1 expression and tissue factor (TF) activity remained unaltered upon SGLT-2 inhibition, and no difference in plasma D-dimer levels was detected, suggesting comparable coagulation cascade activation and fibrinolytic activity. In human aortic endothelial cells pre-treated with LPS, empagliflozin neither changed TF activity nor PAI-1 expression. Accordingly, among patients with established ASCVD or at high CV risk randomized to a daily dose of 10 mg empagliflozin signatures of thrombotic (i.e. TF) and fibrinolytic activity (i.e. PAI-1) remained unchanged, while plasma glucose declined significantly during 3 months of follow-up., Conclusion: SGLT-2 inhibition by empagliflozin does not impact experimental arterial thrombus formation, neither under BSL conditions nor during sustained low-grade inflammation, and has no impact on proxies of thrombotic/fibrinolytic activity in patients with ASCVD. The beneficial pleiotropic effects of empagliflozin are likely independent of pathways mediating arterial thrombosis., Competing Interests: Conflict of interest: L.L. and G.G.C. are coinventors on the International Patent (WO/2020/226993) filed in April 2020 and relating to the use of antibodies, which specifically bind IL-1α to reduce various sequelae of ischaemia–reperfusion injury to the central nervous system. G.G.C. is a consultant to Sovida solutions limited. L.L. has received speaker fees outside of this work from Daichi-Sankyo. T.F.L. has received honoraria and educational grants from Boehringer Ingelheim Switzerland and Ingelheim, FRG, respectively. N.M. has received support for clinical trial leadership from Boehringer Ingelheim, served as a consultant to Boehringer Ingelheim, Merck, AstraZeneca, BMS, received grant support from Boehringer Ingelheim, Merck, and served as a speaker for Boehringer Ingelheim, Merck, Novo Nordisk, Lilly, BMS, and AstraZeneca. M.L. received grants and personal fees from Boehringer Ingelheim, MSD, Novo Nordisk and personal fees from Amgen, Sanofi, Astra Zeneca, Bayer, Lilly, Daiichi Sankyo, Novarits, Amarin. The other authors report no conflict of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Despite devastating clinical sequelae of calcific aortic valve disease that range from left ventricular remodeling to arrhythmias, heart failure, and early death, the molecular insights into disease initiation and progression are limited and pharmacotherapies remain unavailable. The pathobiology of calcific aortic valve disease is complex and comprehensive studies are challenging valvular calcification is heterogeneous and occurs preferentially on the aortic surface, along a fibrocalcific spectrum. Here, we review efforts to study (epi-)genomic, transcriptomic, proteomic, and metabolomic aspects of aortic valve calcification in combination with network medicine-/systems biology-based strategies to integrate multilayered omics datasets and prioritize druggable targets for experimental validation studies. Ultimately, such holistic approach efforts may open therapeutic avenues that go beyond invasive and costly valve replacement therapy.

Objective: Arterial thrombosis may be initiated by endothelial inflammation or denudation, activation of blood-borne elements or the coagulation system. Tissue factor (TF), a central trigger of the coagulation cascade, is regulated by the pro-inflammatory NF-κB-dependent pathways. Sirtuin 6 (SIRT6) is a nuclear member of the sirtuin family of NAD + -dependent deacetylases and is known to inhibit NF-κB signaling. Its constitutive deletion in mice shows early lethality with hypoglycemia and accelerated aging. Of note, the role of SIRT6 in arterial thrombosis remains unknown. Thus, we hypothesized that endothelial SIRT6 protects from arterial thrombosis by modulating inhibition of NF-κB-associated pathways., Approach and Results: Using a laser-induced carotid thrombosis model, in vivo arterial occlusion occurred 45% faster in 12-week-old male endothelial-specific Sirt6 -/- mice as compared to Sirt6 fl/fl controls (n ≥ 9 per group; p = 0.0012). Levels of procoagulant TF were increased in animals lacking endothelial SIRT6 as compared to control littermates. Similarly, in cultured human aortic endothelial cells, SIRT6 knockdown increased TF mRNA, protein and activity. Moreover, SIRT6 knockdown increased mRNA levels of NF-κB-associated genes tumor necrosis factor alpha (TNF-α), poly [ADP-ribose] polymerase 1 (PARP-1), vascular cell adhesion molecule 1 (VCAM-1), and cyclooxygenase-2 (COX-2); at the protein level, COX-2, VCAM-1, TNF-α, and cleaved PARP-1 remained increased after Sirt6 knockdown., Conclusions: Endothelium-specific Sirt6 deletion promotes arterial thrombosis in mice. In cultured human aortic endothelial cells, SIRT6 silencing enhances TF expression and activates pro-inflammatory pathways including TNF-α, cleaved PARP-1, VCAM-1 and COX-2. Hence, endogenous endothelial SIRT6 exerts a protective role in experimental arterial thrombosis., (Copyright © 2022. Published by Elsevier Ltd.)

Background: The Global Registry of Acute Coronary Events (GRACE) 2.0 score was developed and validated in predominantly male patient populations. We aimed to assess its sex-specific performance in non-ST-segment elevation acute coronary syndromes (NSTE-ACS) and to develop an improved score (GRACE 3.0) that accounts for sex differences in disease characteristics., Methods: We evaluated the GRACE 2.0 score in 420 781 consecutive patients with NSTE-ACS in contemporary nationwide cohorts from the UK and Switzerland. Machine learning models to predict in-hospital mortality were informed by the GRACE variables and developed in sex-disaggregated data from 386 591 patients from England, Wales, and Northern Ireland (split into a training cohort of 309 083 [80·0%] patients and a validation cohort of 77 508 [20·0%] patients). External validation of the GRACE 3.0 score was done in 20 727 patients from Switzerland., Findings: Between Jan 1, 2005, and Aug 27, 2020, 400 054 patients with NSTE-ACS in the UK and 20 727 patients with NSTE-ACS in Switzerland were included in the study. Discrimination of in-hospital death by the GRACE 2.0 score was good in male patients (area under the receiver operating characteristic curve [AUC] 0·86, 95% CI 0·86-0·86) and notably lower in female patients (0·82, 95% CI 0·81-0·82; p<0·0001). The GRACE 2.0 score underestimated in-hospital mortality risk in female patients, favouring their incorrect stratification to the low-to-intermediate risk group, for which the score does not indicate early invasive treatment. Accounting for sex differences, GRACE 3.0 showed superior discrimination and good calibration with an AUC of 0·91 (95% CI 0·89-0·92) in male patients and 0·87 (95% CI 0·84-0·89) in female patients in an external cohort validation. GRACE 3·0 led to a clinically relevant reclassification of female patients to the high-risk group., Interpretation: The GRACE 2.0 score has limited discriminatory performance and underestimates in-hospital mortality in female patients with NSTE-ACS. The GRACE 3.0 score performs better in men and women and reduces sex inequalities in risk stratification., Funding: Swiss National Science Foundation, Swiss Heart Foundation, Lindenhof Foundation, Foundation for Cardiovascular Research, and Theodor-Ida-Herzog-Egli Foundation., Competing Interests: Declaration of interests SK received travel support from the European Atherosclerosis Society and equipment and materials from Roche Diagnostics, outside the submitted work. MR declares institutional research grants from Terumo, Biotronik, Medtronic, Cordis/Cardinal Health, and Boston Scientific, outside the submitted work. LR received funding from Abbott, Biotronik, Boston Scientific, Sanofi, Regeneron, and Heartflow, consulting fees from Abbott, Amgen, AstraZeneca, Canon, NovoNordisk, Medtronic, Sanofi, Occlutech, and Vifor, payment or honoraria from Abbott and Occlutech, and travel support from AstraZeneca. MdB is Chair of the Data Monitoring and Ethics Committee of the UK GRIS Trial and part of the Steering Committee of the DAPA MI Trial. CW is the clinical lead of the MINAP registry. JD received consulting fees from GENinCode UK Ltd, honoraria or consulting fees from Amgen, Boehringer Ingelheim, Merck, Pfizer, Aegerion, Novartis, Sanofi, Takeda, Novo Nordisk, and Bayer, and travel support from the Einstein Professorship Foundation (Berlin, Germany), outside the submitted work. JD holds unpaid leadership positions at Our Future Health and Public Health England. TFL declares institutional educational and research grants from Abbott, Amgen, AstraZeneca, Boehringer Ingelheim, Daichi Sankyo, Novartis, and Vifor, and consulting fees from Daichi Sankyo, Philipps, Pfizer, and Ineeo Inc, outside the submitted work. TFL holds leadership positions at the European Society of Cardiology, Swiss Heart Foundation, and the Foundation for Cardiovascular Research—Zurich Heart House. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Aims: The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) and its shedding product [soluble LOX-1 (sLOX-1)] are implicated in atherosclerotic cardiovascular disease (ASCVD) pathogenesis. Herein, we examined the relationship of sLOX-1 with both fatal events and plaque progression in patients with acute coronary syndromes (ACS)., Methods and Results: Plasma sLOX-1 was assessed at baseline in ACS and chronic coronary syndrome (CCS) patients prospectively recruited in the multicentre SPUM-ACS study, with sex- and age-matched healthy subjects serving as additional controls (n = 2924). Compared with both CCS and controls, ACS patients showed markedly elevated sLOX-1 levels (median, 2.00 and 2.00 vs. 35.08 pg/mL; P < 0.0001) which were independently associated with increased mortality risk over 30-day [tertile (T)3: adjusted hazard ratio (HR), 3.11; 95% confidence interval (CI), 1.44-10.61; P = 0.0055] and 1-year intervals (T3: adjusted HR, 2.04; 95% CI, 1.19-3.92; P = 0.0098). Results remained consistent after adjustment for GRACE 2.0 (T3: adjusted HR, 1.86; 95% CI, 1.04-3.74; P = 0.0391) and were primarily driven by the pronounced relationship of sLOX-1 with cardiovascular mortality at 30 days (T3: adjusted HR, 3.81; 95% CI, 1.62-19.62; P = 0.0036) and at 1 year (T3: adjusted HR, 2.29; 95% CI, 1.19-5.34; P = 0.0148). In ACS patients undergoing serial intracoronary imaging and statin therapy, sLOX-1 dropped significantly in those with coronary plaque regression at 1 year (ΔsLOX-1: -4.64 ± 1.80; P = 0.0057), and showed a good discrimination for predicting plaque progression (area under the curve = 0.74; 95% CI, 0.59-0.86; P = 0.0031)., Conclusion: Plasma sLOX-1 levels are increased during ACS and predict fatal events beyond traditional and emerging risk factors. Persistently high sLOX-1 associates with coronary plaque progression in patients with established ASCVD., Clinical Trial Registration: NCT01000701., (© The Author(s) 2022. Published by Oxford University Press on behalf of European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)