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Clinical medicine requires the integration of various forms of patient data including demographics, symptom characteristics, electrocardiogram findings, laboratory values, biomarker levels, and imaging studies. Decision-making on the optimal management should be based on a high probability that the envisaged treatment is appropriate, provides benefit, and bears no or little potential harm. To that end, personalized risk-benefit considerations should guide the management of individual patients to achieve optimal results. These basic clinical tasks have become more and more challenging with the massively growing data now available; artificial intelligence and machine learning (AI/ML) can provide assistance for clinicians by obtaining and comprehensively preparing the history of patients, analysing face and voice and other clinical features, by integrating laboratory results, biomarkers, and imaging. Furthermore, AI/ML can provide a comprehensive risk assessment as a basis of optimal acute and chronic care. The clinical usefulness of AI/ML algorithms should be carefully assessed, validated with confirmation datasets before clinical use, and repeatedly re-evaluated as patient phenotypes change. This review provides an overview of the current data revolution that has changed and will continue to change the face of clinical medicine radically, if properly used, to the benefit of physicians and patients alike., (© 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: Conflict of interest: T.F.L. and F.W. have no conflicts of interest related to this manuscript. Outside this work. T.F.L. has received educational and research grants to the institution from Abbott, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Daichi-Sankyo, Eli Lilly, Novartis, Novo Nordisk, Sanofi, Vifor.

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.)

Background: The primary aim of this study was to assess 30-day and 1-year rates for unplanned readmission due to implant-associated complications following total hip (THA) or total knee arthroplasty (TKA) in Austria. Secondary endpoints were reasons for readmission and differences in revision risk depending on demographics and hospital size., Methods: Data on patients receiving THA (n = 18,508) or TKA (n = 15,884) in orthopaedic and trauma units across Austria within a 1-year period (January 2021 to December 2021) were retrieved from a government-maintained database. The absolute and relative frequencies of unplanned readmissions were calculated. Risk factors for 30-day and 1-year readmission following THA or TKA due to implant-associated complications were investigated., Results: The 30-day and 1-year readmission rates for any implant-associated complication were 1.0% (339 of 34,392) and 3.0% (1,024 of 34,392), respectively. Relative to the overall readmission rate for any complication at 30 days (n = 1,952) and 1 year (n = 12,109), readmission rates for implant-associated complications were 17.4 and 8.5%, respectively. The 30-day readmission rates were higher in THA (1.2%) than TKA patients (0.8%; P = 0.001), while it was the opposite at 1 year (THA, 2.7%; TKA, 3.3%; P < 0.001). Mechanical complications (554 of 1,024) were the most common reason for 1-year readmission. Prolonged length of in-hospital stay independently associated with increased 1-year readmission risk in THA and TKA patients. Treatment at large-sized hospitals was associated with a higher 1-year readmission risk in TKA patients., Conclusions: The 30-day and 1-year readmission rates for implant-associated complications following THA or TKA in Austria are lower than reported in other countries, with similar risk factors and reasons for readmission. Considering that almost 20% of unplanned hospital readmissions following total joint arthroplasty are attributable to implant-associated complications, optimization of in-hospital and postdischarge medical care for these patients is warranted., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Due to its peculiar structure and function, the cardiovascular system is particularly vulnerable to the detrimental effects of ageing. Current knowledge about the molecular mechanisms of ageing revealed the processes actively promoting ageing, e.g. progressive telomeres shortening, and the mechanisms opposing it, e.g. endogenous production of antioxidant substances. This knowledge can be used to measure biological age at a cellular and molecular level and to interfere with it by pharmacological or non-pharmacological interventions. Biological ageing is determined by the simultaneous occurrence of independent hallmarks, which encompass a wide range of biological processes, from genomic changes to systemic inflammation and dysbiosis. This narrative review will summarize the role of ageing hallmarks in the cardiovascular system, how they can be measured and what are the possible interventions to counteract their effects., (© 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: 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: 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.)

Background: Carnitine metabolism produces numerous molecular species of short-, medium-, and long-chain acylcarnitines, which play important roles in energy homeostasis and fatty acid transport in the myocardium. Given that disturbances in the carnitine metabolism are linked to cardiometabolic disease, we studied the relationship of circulating acylcarnitines with outcomes in patients with acute coronary syndromes (ACS) and evaluated differences in circulating levels of these metabolites between diabetic and non-diabetic patients., Methods: Harnessing a prospective multicentre cohort study (SPUM-ACS; NCT01000701), we measured plasma levels of acylcarnitines, carnitine, and carnitine metabolites to assess their relationship with adjudicated major adverse cardiac events (MACE), defined as composite of myocardial infarction, stroke, clinically indicated revascularization, or death of any cause. The SPUM-ACS study enrolled patients presenting with ACS to Swiss University Hospitals between 2009 and 2012. Acetylcarnitine, octanoylcarnitine, proprionylcarnitine, butyrylcarnitine, pentanoylcarnitine, hexanoylcarnitine, carnitine, γ-butyrobetaine, and trimethylamine N-oxide were measured in plasma using stable isotope dilution high-performance liquid chromatography with online electrospray ionization tandem mass spectrometry., Results: A total of 1683 patients with ACS were included in the study. All measured metabolites except γ-butyrobetaine and carnitine were higher in diabetic subject (n = 294) than in non-diabetic subjects (n = 1389). On univariate analysis, all metabolites, apart from octenoylcarnitine, were significantly associated with MACE at 1 year. After multivariable adjustment for established risk factors, acetylcarnitine remained an independent predictor of MACE at 1-year (quartile 4 vs. quartile 1, adjusted hazard ratio 2.06; 95% confidence interval 1.12-3.80, P = 0.020)., Conclusion: Circulating levels of acetylcarnitine independently predict residual cardiovascular risk in patients with ACS., (Copyright © 2023 Elsevier B.V. All rights reserved.)

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 ST-segment elevation typically feature total coronary occlusion (TCO) of the infarct-related artery (IRA) on angiography, which may result in worse outcomes. Yet, relying solely on electrocardiogram (ECG) findings may be misleading and those presenting with non-ST-segment elevation acute coronary syndromes (NSTE-ACSs) may have TCO as well. Herein, we aimed to delineate clinical characteristics and outcomes of patients with ACS stratified by IRA location., Methods: A total of 4787 ACS patients were prospectively recruited between 2009 and 2017 in SPUM-ACS (ClinicalTrials.gov Identifier: NCT01000701). The primary endpoint was major adverse cardiovascular events (MACEs), a composite of all-cause death, non-fatal myocardial infarction and non-fatal stroke at 1 year. Multivariable-adjusted survival models were fitted using backward selection., Results: A total of 4412 ACS patients were included in this analysis, 56.0% (n = 2469) ST-elevation myocardial infarction (STEMI) and 44.0% (n = 1943) NSTE-ACS. The IRA was the right coronary artery (RCA) in 33.9% (n = 1494), the left-anterior descending coronary artery (LAD) in 45.6% (n = 2013), and the left circumflex (LCx) in 20.5% (n = 905) patients. In STEMI patients, TCO (defined as TIMI 0 flow at angiography) was observed in 55% of cases with LAD, in 63% with RCA, and in 55% with LCx. In those presenting with NSTE-ACS, TCO was more frequent in those with LCx and RCA as compared to the LAD (27 and 24%, respectively, vs. 9%, P < 0.001). Among patients with NSTE-ACS, occlusion of the LCx was associated with an increased risk of MACE during 1 year after the index ACS (fully adjusted hazard ratio 1.68, 95% confidence interval 1.10-2.59, P = 0.02; reference: RCA and LAD). Features of patients with NSTE-ACS associated with TCO of the IRA included elevated lymphocyte and neutrophil counts, higher levels of high-sensitivity C reactive protein (hs-CRP) and high-sensitivity cardiac troponin T, lower eGFR, and notably a negative history of MI., Conclusion: In NSTE-ACS, both LCx and RCA involvement was associated with TCO at angiography despite the absence of ST-segment elevation. Involvement of the LCx, but not the LAD or RCA, as the IRA represented an independent predictor of MACE during 1-year follow-up. Hs-CRP, lymphocyte, and neutrophil counts were independent predictors of total IRA occlusion, suggesting a possible role of systemic inflammation in the detection of TCO irrespective of ECG presentation., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

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 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.)

Objective: Long noncoding RNAs (lncRNAs) are involved in diabetogenesis in experimental models, yet their role in humans is unclear. We investigated whether circulating lncRNAs associate with incident type 2 diabetes in older adults., Research Design and Methods: A preselected panel of lncRNAs was measured in serum of individuals without diabetes (n = 296) from the Vienna Transdanube Aging study, a prospective community-based cohort study. Participants were followed up over 7.5 years. A second cohort of individuals with and without type 2 diabetes (n = 90) was used to validate our findings., Results: Four lncRNAs (ANRIL, MIAT, RNCR3, and PLUTO) were associated with incident type 2 diabetes and linked to hemoglobin A1c trajectories throughout the 7.5-year follow-up. Similar results (for MIAT and PLUTO also in combined analysis) were obtained in the validation cohort., Conclusions: We found a set of circulating lncRNAs that independently portends incident type 2 diabetes in older adults years before disease onset., (© 2023 by the American Diabetes Association.)

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.)

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.)

Introduction: Traumatic penetrating arteriovenous fistulas (AVFs) are very rare. The majority of these injuries occur secondary to penetrating trauma. Objectives of this study: review their incidence, clinical presentation, radiologic identification, management, complications and outcomes., Methods: A literature search was performed on MEDLINE Complete-Pubmed from 1829-2019. PRISMA guidelines were utilized. Of 305 potentially eligible articles, 201 articles were selected., Inclusion Criteria: patients age ≥ 18, articles with title and abstract in English, AVFs secondary to penetrating trauma, articles which specified vessels involved in AVFs, and those reporting complete information on patient presentation, diagnosis, imaging, surgical and/or endovascular surgical management, and outcomes of penetrating AVF's., Exclusion Criteria: articles reporting blunt or iatrogenic AVFs, pediatric patients, fistulas used for dialysis and their complications, articles lacking complete information, cranial/spinal AVFs or cardiac AVFs, and duplicate articles. Mechanism of injury (MOI), diagnosis, involved vessels, management and outcomes of patients with AVFs secondary to penetrating trauma were recorded., Results: There were a total of 291 patients with AVFs secondary to penetrating injuries. Mechanism of injury (MOI): stab wounds (SW)-126 (43.3%), Gunshot wounds (GSW)-94 (32.3%), miscellaneous-35 (12%), mechanism unspecified-36 (12.4%). Anatomic area: neck-69 (23.7%) patients, thorax-46 (15.8%), abdomen-87 (30%), upper and lower extremities-89 (30.6%). Most commonly involved vessels-vertebral artery-38 (13%), popliteal vein-32 (11.7%). Angiography was diagnostic-265 patients (91.1%)., Interventions: Surgical- 202 (59.6%), Endovascular-118 (34.8%). Associated: aneurysms/pseudoaneurysms-129 (44.3%)., Conclusion: Most AVFs occur secondary to penetrating injuries. Stab wounds account for the majority of these injuries. Most frequently injured vessels are vertebral artery and superficial femoral vein. Surgical interventions are the most common mode of management followed by endovascular surgical techniques., (© 2021. Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: Therapeutic modulation of blood vessel growth holds promise for the prevention of limb ischemia in diabetic (DM) patients with peripheral artery disease (PAD). Epigenetic changes, namely, posttranslational histone modifications, participate in angiogenic response suggesting that chromatin-modifying drugs could be beneficial in this setting. Apabetalone (APA), a selective inhibitor of bromodomain (BRD) and bromodomain and extraterminal containing protein family (BET) proteins, prevents bromodomain-containing protein 4 (BRD4) interactions with chromatin thus modulating transcriptional programs in different organs. We sought to investigate whether APA affects angiogenic response in diabetes. Results: Compared with vehicle, APA restored tube formation and migration in human aortic endothelial cells (HAECs) exposed to high-glucose (HG) levels. Expression profiling of angiogenesis genes showed that APA prevents HG-induced upregulation of the antiangiogenic molecule thrombospondin-1 (THBS1). ChIP-seq and chromatin immunoprecipitation (ChIP) assays in HG-treated HAECs showed the enrichment of both BRD4 and active marks (H3K27ac) on THBS1 promoter, whereas BRD4 inhibition by APA prevented chromatin accessibility and THBS1 transcription. Mechanistically, we show that THBS1 inhibits angiogenesis by suppressing vascular endothelial growth factor A (VEGFA) signaling, while APA prevents these detrimental changes. In diabetic mice with hind limb ischemia, epigenetic editing by APA restored the THBS1/VEGFA axis, thus improving limb vascularization and perfusion, compared with vehicle-treated animals. Finally, epigenetic regulation of THBS1 by BRD4/H3K27ac was also reported in DM patients with PAD compared with nondiabetic controls. Innovation: This is the first study showing that BET protein inhibition by APA restores angiogenic response in experimental diabetes. Conclusions: Our findings set the stage for preclinical studies and exploratory clinical trials testing APA in diabetic PAD. Antioxid. Redox Signal. 36, 667-684.

Overlapping pandemics of lifestyle-related diseases pose a substantial threat to cardiovascular health. Apart from coronary artery disease, metabolic disturbances linked to obesity, insulin resistance and diabetes directly compromise myocardial structure and function through independent and shared mechanisms heavily involving inflammatory signals. Accumulating evidence indicates that metabolic dysregulation causes systemic inflammation, which in turn aggravates cardiovascular disease. Indeed, elevated systemic levels of pro-inflammatory cytokines and metabolic substrates induce an inflammatory state in different cardiac cells and lead to subcellular alterations thereby promoting maladaptive myocardial remodeling. At the cellular level, inflammation-induced oxidative stress, mitochondrial dysfunction, impaired calcium handling, and lipotoxicity contribute to cardiomyocyte hypertrophy and dysfunction, extracellular matrix accumulation and microvascular disease. In cardiometabolic patients, myocardial inflammation is maintained by innate immune cell activation mediated by pattern recognition receptors such as Toll-like receptor 4 (TLR4) and downstream activation of the NLRP3 inflammasome and NF-κB-dependent pathways. Chronic low-grade inflammation progressively alters metabolic processes in the heart, leading to a metabolic cardiomyopathy (MC) phenotype and eventually to heart failure with preserved ejection fraction (HFpEF). In accordance with preclinical data, observational studies consistently showed increased inflammatory markers and cardiometabolic features in patients with HFpEF. Future treatment approaches of MC may target inflammatory mediators as they are closely intertwined with cardiac nutrient metabolism. Here, we review current evidence on inflammatory processes involved in the development of MC and provide an overview of nutrient and cytokine-driven pro-inflammatory effects stratified by cell type., 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 © 2021 Wenzl, Ambrosini, Mohammed, Kraler, Lüscher, Costantino and Paneni.)

Objective: Traumatic arteriovenous fistulas (AVFs) are rare. The vast majority occur secondary to penetrating injuries. High-output cardiac failure is a well-recognized serious complication of AVFs, associated with high morbidity and mortality. The objective of the present study was to identify predictors of heart failure (HF) in patients with traumatic AVF., Methods: Both PubMed/MEDLINE (Ovid) and CINAHL were searched (up to June 2019) for studies reporting individual patient data on the clinical and demographic characteristics of patients with AVF secondary to penetrating trauma. Exclusion criteria were age <18 years, no specification of symptoms, a cranial, spinal, or cardiac AVF location, and an iatrogenic mechanism of injury. The present study was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines., Results: A total of 274 AVF patients from 15 case series and 177 case reports were included. The median age at presentation was 32 years (interquartile range, 24-43 years), 90% were men. The most frequent mechanisms of injury were stab wounds (43%) and gunshot wounds (32%). The AVF location was the abdomen (n = 86; 31%), lower limb (n = 79; 29%), neck (n = 61; 22%), thorax (n = 38; 14%), and upper limb (n = 10; 4%). Of the 274 patients, 35 (13%) had presented with HF and 239 (87%) with other symptoms. The risk of HF increased with an increased feeding artery diameter (P < .001). On univariate analysis, HF was significantly associated with a longer median time from injury to presentation with AVF (11.2 years vs 0.1 years; P < .001), older median age at presentation (43 years vs 31 years; P = .002), involvement of a large feeding artery (ie, aorta, pulmonary artery, subclavian artery, external iliac artery; 40% vs 13%; P < .001), shrapnel injuries (11% vs 2%; P = .011), and injuries to the trunk or lower limb (94% vs 71%; P = .004). After adjusting for clinical and demographic patient characteristics, involvement of a large feeding artery (odds ratio, 3.25; 95% confidence interval, 1.26-8.42; P = .015) and every 6 years of delay to presentation (odds ratio, 1.30; 95% confidence interval, 1.03-1.63; P = .026) remained independent predictors for HF., Conclusions: HF occurs in a small but important fraction of traumatic AVF patients and develops after highly variable latency periods. Large feeding arteries and delayed presentation independently predicted HF in this cohort., (Copyright © 2020 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)

Background: Brachial artery injuries are rare. The objectives of the study are to report our experience and identify predictors of outcome. The hypothesis of the study is that maintaining ischemic times less than six hours results in improved outcomes., Methods: This is a retrospective 118-month study. The outcome measure is total operative time from admission to restoration of blood flow, and outcomes are survival and limb salvage. Statistical analyses used in the study are univariate and multivariate stepwise logistic regression., Results: There were 124 patients with 131 brachial artery injuries. Mechanism of injury (MOI) included the following: penetrating: 108 (87%) and blunt: 16 (13%). Operative management included the following: 77 (62%) reverse saphenous vein interposition grafts, 37 (29.8%) end-to-end anastomosis, and 4 (3.2%) ligation. Fasciotomies were performed in 23 (19.2%) patients. Outcomes of the study were as follows: 120 patients survived and the overall survival rate was 96.8%, adjusted survival rate excluding intraoperative deaths was 100%, overall limb salvage/amputation rate was 95.1%/4.9%, and adjusted limb salvage/amputation rates excluding intraoperative deaths were 98.3%/1.67%. Univariate analysis showed the mean ischemic times for survivors as 5 ± 3.1 hrs (300 ± 186 min) versus ischemic times for non survivors as 3 ± 2.2 hrs (180 ± 132 min) (P = 0.017); Injury Severity Score (ISS) (P = 0.002); and estimated blood loss (EBL) (P = 0.024). Logistic regression identified independent predictors of outcome for survival: MOI: penetrating [P = 0.015, RR - 4.29, 95% CI: 1.49-12.36]; Glasgow Coma Score < 7 [P < 0.001, RR - 21.71, 95% CI: 9.37-50.32]; ISS > 15 [P < 0.005, RR - 4.98, 95% CI: 1.68-14.73]; and patients not requiring ED thoracotomy [P = 0.009, RR - 7.48, 95% CI: 2.58-21.69]., Conclusions: Brachial artery injuries are rare. For patients not requiring ED thoracotomy, Glasgow Coma Score, ISS, and EBL predicted survival. The adjusted limb salvage rate was 98.3%. Patients with brachial artery injuries die from associated injuries, experiencing less ischemic times than survivors who are able to undergo repairs., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Popliteal artery injuries are rare. They have high amputation rates., Objectives: To report our experience, identify predictors of outcome; mechanism of injury (MOI), Mangled Extremity Severity Score (MESS) score and length of ischemic time. We hypothesized that ischemic time as close to six hours results in improved outcomes., Methods: Retrospective 132-month study. All popliteal artery injuries. Urban Level I Trauma Center., Outcome Measures: MOI, ISS, MESS, ischemic time, risk factors for amputation, role of popliteal venous injuries, and limb salvage., Statistical Analysis: univariate and multivariate., Results: 76 patients - 59 (76.1%) males and 17 (22.4%) females. MOI: penetrating - 54 (71%). MESS for penetrating injuries - 5.8 ± 1.5, blunt injuries - 5.6 ± 1.8. Admission-perfusion restoration (n = 76) - 5.97 hours (358 minutes). Ischemic time was not predictive of outcome (p = 0.79). Ischemic time penetrating (n = 58) 5.9 hours (354 ± 209 minutes), blunt 6.1 hours (371 ± 201 minutes). Popliteal arterial repairs: RSVG 44 (58%), primary repair 21 (26%), PTFE 3 (4%), vein patch 2 (2%), ligation 2 (3%), exsanguinated 4 (6%). No patients underwent stenting. Popliteal Vein: Repair 19 (65%), ligation 10 (35%). Fasciotomies 45 patients (59%)., Outcomes: Limb salvage - 90% (68/76). Adjusted limb salvage excluding intraoperative deaths - 94% (68/72). Selected patient characteristics; MOI: penetrating vs. blunt - age (p <0.0005). Amputated vs. non-amputated patients, age (p < 0.05). ISS (p < 0.005) predicted amputation, MESS (p = 0.98) did not. Mean ischemic time (p = 0.79) did not predict amputation. Relative risk of amputation, MOI - blunt (p = 0.26, RR 4.67, 95% CI: 1.11 - 14.1), popliteal artery ligation (p = 0.06, RR 3.965, 95% CI: 1.11 - 14.1) as predictors of outcome. Combined artery and vein injuries (p = 0.25) did not predict amputation., Conclusions: Decreasing ischemic time from arrival to restoration of perfusion may lead to improved outcomes and increased limb salvage. MESS is not predictive for amputation. Blunt MOI is a risk factor for amputation. Maintaining ischemic times as close to six hours as possible may lead to improved outcomes., (Copyright © 2020. Published by Elsevier Ltd.)

Background: Penetrating vertebral artery injuries (VAIs) are rare. Because of their rarity, complex anatomy, and difficult surgical exposures, few surgeons and trauma centers have developed significant experience with their management. The objectives of this study were to review their incidence, clinical presentation, radiologic identification, management, complications, and outcomes and to provide a review of anatomic exposures and surgical techniques for their management., Methods: A literature search on MEDLINE Complete-PubMed, Cochrane, Ovid, and Embase for the period of 1893 to 2018 was conducted. Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were used. Our literature search yielded a total of 181 potentially eligible articles with 71 confirmed articles, consisting of 21 penetrating neck injury series, 13 VAI-specific series, and 37 case reports. Operative procedures and outcomes were recorded along with methods of angiographic imaging and operative management. All articles were reviewed by at least two independent authors, and data were analyzed collectively., Results: There were a total of 462 patients with penetrating VAIs. The incidence of VAI in the civilian population was 3.1% vs 0.3% in the military population. More complete data were available from 13 collected VAI-specific series and 37 case reports for a total of 362 patients. Mechanism of injury data were available for 341 patients (94.2%). There were gunshot wounds (178 patients [49.2%]), stab wounds (131 [73.6%]), and miscellaneous mechanisms of injury (32 [8.8%]). Anatomic site of injury data were available for 177 (49%) patients: 92 (25.4%) left, 84 (23.2%) right, and 1 (0.3%) bilateral. Anatomic segment of injury data were available for 204 patients (56.4%): 28 (7.7%) V1, 125 (34.5%) V2, and 51 (14.1%) V3. Treatment data were available for 212 patients. Computed tomography angiography was the most common imaging modality (163 patients [77%]). Injuries were addressed by operative management (94 [44.3%]), angiography and angioembolization (72 [34%]), combined approaches (11 [5.2%]), and observation (58 [27.4%]). Stenting and repair were less frequently employed (10 [4.7%]). The incidence of aneurysms or pseudoaneurysms was 18.5% (67); the incidence of arteriovenous fistula was 16.9% (61). The calculated mortality in VAI-specific series was 15.1%; in the individual case report group, it was 10.5%., Conclusions: The majority of VAIs present without neurologic symptoms, although some may present with exsanguinating hemorrhage. Computed tomography angiography should be considered first line to establish diagnosis. Gunshot wounds account for most injuries. The most frequently injured segment is V2. Surgical ligation is the most common intervention, followed by angioembolization, both of which constitute important management approaches., (Copyright © 2019 Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.)