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With the increasing burden of diabetes as a cause of macro- and microvascular disease linked to the epidemics of obesity, attention is being paid to dysglycaemic states that predict and precede the development of type 2 diabetes. Such conditions, termed pre-diabetes, are characterized by fasting plasma glucose, or plasma glucose levels on an oral glucose tolerance test, or values of glycated haemoglobin intermediate between 'normal' values and those characterizing diabetes. These last are by definition associated, in epidemiological terms, with a higher incidence of microvascular disease-mostly retinopathy. Pre-diabetes overlaps with the components of the 'metabolic syndrome'-among which are excess visceral adiposity; hypertension; hypertriglyceridaemia; high levels of small, dense low-density lipoproteins; and metabolic-associated fatty liver disease. There is little doubt that pre-diabetes has important prognostic implications, especially for the occurrence of myocardial infarction, ischaemic stroke, and peripheral arterial disease. It is disputed, however, whether pre-diabetes is itself an actionable disease entity, in addition to the risk factors characterizing it. Because of this uncertainty, the latest European Society of Cardiology guidelines chose not to include pre-diabetes as a treatment target for atherosclerotic cardiovascular disease, at variance from the three previous editions of such guidelines. This is spurring a debate, the Pro and Contra arguments featured in the present debate article., (© 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.)

Since the 1960s, cardiologists have adopted several binary classification systems for acute myocardial infarction (MI) that facilitated improved patient management. Conversely, for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology-e.g. 'stable coronary artery disease' (CAD), 'stable ischaemic heart disease', and 'chronic coronary syndromes' (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with 'acute coronary syndromes' (ACS), the 2023 American guidelines endorsed the alternative term 'chronic coronary disease'. An unintended consequence of these competing classifications is perpetuation of the restrictive terms 'coronary' and 'disease', often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. We, therefore, propose a new binary classification of 'acute myocardial ischaemic syndromes' and 'non-acute myocardial ischaemic syndromes', which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. We herein retain accepted categories of ACS, ST-segment elevation MI, and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia and infarction., (Published by Oxford University Press on behalf of the European Society of Cardiology 2024.)

Multivessel coronary artery disease is present in ∼50% of patients with acute coronary syndrome and, compared with single-vessel disease, entails a higher risk of new ischaemic events and a worse prognosis. Randomized controlled trials have shown the superiority of 'complete revascularization' over culprit lesion-only treatment. Trials, however, only included patients treated with percutaneous coronary intervention (PCI), and evidence regarding complete revascularization with coronary artery bypass graft (CABG) surgery after culprit lesion-only PCI ('hybrid revascularization') is lacking. The CABG after PCI is an open, non-negligible therapeutic option, for patients with non-culprit left main and/or left anterior descending coronary artery disease where evidence in chronic coronary syndrome patients points in several cases to a preference of CABG over PCI. This valuable but poorly studied 'PCI first-CABG later' option presents, however, relevant challenges, mostly in the need of interrupting post-stenting dual antiplatelet therapy (DAPT) for surgery to prevent excess bleeding. Depending on patients' clinical characteristics and coronary anatomical features, either deferring surgery after a safe interruption of DAPT or bridging DAPT interruption with intravenous short-acting antithrombotic agents appears to be a suitable option. Off-pump minimally invasive surgical revascularization, associated with less operative bleeding than open-chest surgery, may be an adjunctive strategy when revascularization cannot be safely deferred and DAPT is not interrupted. Here, the rationale, patient selection, optimal timing, and adjunctive strategies are reviewed for an ideal approach to hybrid revascularization in post-acute coronary syndrome patients to support physicians' choices in a case-by-case patient-tailored approach., (© 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.)

Aspirin has been known for a long time and currently stays as a cornerstone of antithrombotic therapy in cardiovascular disease. In patients with either acute or chronic coronary syndromes undergoing percutaneous coronary intervention aspirin is mandatory in a dual antiplatelet therapy regimen for prevention of stent thrombosis and/or new ischaemic events. Aspirin is also currently a first-option antithrombotic therapy after an aortic prosthetic valve replacement and is occasionally required in addition to oral anticoagulants after implantation of a mechanical valve. Presumed or demonstrated aspirin hypersensitivity is a main clinical problem, limiting the use of a life-saving medication. In the general population, aspirin hypersensitivity has a prevalence of 0.6%-2.5% and has a plethora of clinical presentations, ranging from aspirin-exacerbated respiratory disease to anaphylaxis. Although infrequent, when encountered in clinical practice aspirin hypersensitivity poses for cardiologists a clinical dilemma, which should never be trivialized, avoiding-as much as possible-omission of the drug. We here review the epidemiology of aspirin hypersensitivity, provide an outline of pathophysiological mechanisms and clinical presentations, and review management options, starting from a characterization of true aspirin allergy-in contrast to intolerance-to suggestion of desensitization protocols., (© 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.)

Aims: We performed quality control of lipid-lowering therapy (LLT) in patients with acute coronary syndrome (ACS), with a view to proposing corrective actions., Methods and Results: Using a Define Measure Analysis Improve Control (DMAIC) approach applied to data from the ACS EuroPath IV survey, we measured attainment of two quality indicators (QIs) related to lipid-lowering treatment: (i) prescription of high-intensity statins (or equipotent treatment) before discharge, and (ii) proportion with LDL-cholesterol <55 mg/dL (1.4 mmol/L) during follow-up. A total of 530 European cardiologists responded and provided data for up to 5 patients from their centre, for acute and follow-up phases. Corrective measures are proposed to increase the rate of attainment of both QIs. Attainment of the first QI was measured in 929 acute-phase patients, 99% had LLT prescribed at discharge and 75% of patients fulfilled the first QI. Attainment of the second QI was assessed in 1721 patients with follow-up. The second QI was reached in 31% of patients. The DMAIC approach yielded 10 potential changes in prescription, 3 for the first and 7 for the second QI. The overall strategy is 'Fire to Target', i.e. early intensification of the LLT using statins, ezetimibe, bempedoic acid, and proprotein convertase subtilisin/kexin type-9 inhibitors, and is presented as an algorithm for routine application., Conclusion: Quality control for LLT, based on the ACS EuroPath IV survey, detected 10 potential changes in prescription that could enhance attainment of 2 QIs. Whether the Fire to Target strategy will be adopted and effective needs to be assessed in further steps of the EuroPath Quality programme., Competing Interests: Conflict of interest: F.S. has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amgen, Bayer, Novartis, Novo Nordisk, Sanofi Aventis, Recordati, Servier, Mylan, and AstraZeneca. A.S. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Ferrer, Getinge, Novartis, Pfizer, Sanofi, and Zoll. A.L.C. has received honoraria, lecture fees, or research grants from: AstraZeneca, Aegerion, Amryt, Amarin, Daiichi Sankyo, Esperion, Ionis Pharmaceuticals, Kowa, Medscape, Mylan, Merck, Menarini, Novartis, Peer Voice, Pfizer, Recordati, Regeneron, Sandoz, Sanofi, and The Corpus. The work of A.L.C. relevant to this publication is supported by Ministero della salute Ricerca corrente. R.D.C. has received honoraria, lecture fees, or research grants from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Roche, Novartis, AstraZeneca, Milestone, Menarini, Guidotti, Lilly, Merck, and Portola. U.L. has received honoraria, lecture fees, or research grants from Amgen, Daiichi Sankyo, Novartis, and Sanofi. A.Z. has received honoraria, consulting, or lecture fees from Sanofi, Amgen, and Novartis. J.W.J. and his department has received research grants from and/or was speaker (with or without lecture fees) on a.o. (CME accredited) meetings sponsored by Amarin, Amgen, Athera, Biotronik, Boston Scientific, Dalcor, Daiichi Sankyo, Lilly, Medtronic, Merck-Schering-Plough, Novartis, Novo Nordisk, Pfizer, Roche, Sanofi Aventis, The Netherlands Heart Foundation, CardioVascular Research The Netherlands (CVON), The Netherlands Heart Institute, and the European Community Framework KP7 Programme., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: We measured myocardial T2 values by a segmental approach in thalassaemia major (TM) patients, comparing such values against T2* values for the detection of myocardial iron overload (MIO), evaluating their potential in detecting subclinical inflammation, and correlating with clinical status., Methods and Results: One-hundred and sixty-six patients (102 females, 38.29 ± 11.49years) enrolled in the Extension-Myocardial Iron Overload in Thalassemia Network underwent magnetic resonance imaging for the assessment of hepatic, pancreatic, and cardiac iron overload (T2* technique), of biventricular function (cine images), and of replacement myocardial fibrosis [late gadolinium enhancement (LGE)]. T2 and T2* values were quantified in all 16 myocardial segments, and the global value was the mean of all segments. Global heart T2 values were significantly higher in TM than in a cohort of 80 healthy subjects. T2 and T2* values were significantly correlated. Out of the 25 patients with a decreased global heart T2* value, 11 (44.0%) had reduced T2 values. No patient with a normal T2* value had a decreased T2 value.Eleven (6.6%) patients had a decreased global heart T2 value, 74 (44.6%) a normal global heart T2 value, and 81 (48.8%) an increased global heart T2 value. Biventricular function was comparable amongst the three groups, whilst LGE was significantly more frequent in patients with reduced vs. increased global heart T2 value. Compared with the other two groups, patients with reduced T2 values had significantly higher hepatic and pancreatic iron deposition., Conclusion: In TM, T2 mapping does not offer any advantage in terms of sensitivity for MIO assessment but detects subclinical myocardial inflammation., Competing Interests: Conflict of interest: AP received speakers’ honoraria from Chiesi Farmaceutici S.p.A. The remaining authors have nothing to disclose., (© 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.)

Aims: Heart failure (HF) is a risk factor for major adverse events in atrial fibrillation (AF). Whether this risk persists on non-vitamin K antagonist oral anticoagulants (NOACs) and varies according to left ventricular ejection fraction (LVEF) is debated., Methods and Results: We investigated the relation of HF in the ETNA-AF-Europe registry, a prospective, multicentre, observational study with an overall 4-year follow-up of edoxaban-treated AF patients. We report 2-year follow-up for ischaemic stroke/transient ischaemic attack (TIA)/systemic embolic events (SEE), major bleeding, and mortality. Of the 13 133 patients, 1854 (14.1%) had HF. Left ventricular ejection fraction was available for 82.4% of HF patients and was <40% in 671 (43.9%) and ≥40% in 857 (56.1%). Patients with HF were older, more often men, and had more comorbidities. Annualized event rates (AnERs) of any stroke/SEE were 0.86%/year and 0.67%/year in patients with and without HF. Compared with patients without HF, those with HF also had higher AnERs for major bleeding (1.73%/year vs. 0.86%/year) and all-cause death (8.30%/year vs. 3.17%/year). Multivariate Cox proportional models confirmed HF as a significant predictor of major bleeding [hazard ratio (HR) 1.65, 95% confidence interval (CI): 1.20-2.26] and all-cause death [HF with LVEF <40% (HR 2.42, 95% CI: 1.95-3.00) and HF with LVEF ≥40% (HR 1.80, 95% CI: 1.45-2.23)] but not of ischaemic stroke/TIA/SEE., Conclusion: Anticoagulated patients with HF at baseline featured higher rates of major bleeding and all-cause death, requiring optimized management and novel preventive strategies. NOAC treatment was similarly effective in reducing risk of ischaemic events in patients with or without concomitant HF., Competing Interests: Conflict of interest: R.B.S. has received lecture fees and advisory board fees from BMS/Pfizer outside this work. P.A. has received lecture and/or advisory board fees from Daiichi Sankyo, Boehringer Ingelheim, Novartis, AstraZeneca, Janssen, MSD, Vifor, and Bayer. J.M.S.-M. has received speaker or consultant fees by AOP, Chiesi, Biosensors, Boston Scientific, P&F, Boehringer Ingelheim, and Daiichi Sankyo not related to the submitted work. I.D. reports having received speaker fees from Daiichi Sankyo and Pfizer. M.G. has received personal fees (lectures, advisory boards, and research grants) and travel grants from Daiichi Sankyo, Boehringer Ingelheim, Bayer, Abbott, Biotronik, Boston, Medtronic, and Sorin. L.P. has received fees from Daiichi Sankyo, Beckman-Coulter, and SOTIO. M.C.M. and J.S. are employees of Daiichi Sankyo Europe GmbH, Munich, Germany. R.D.C. reports grants, personal fees, and non-financial support from Daiichi Sankyo, during the conduct of the study, and reports consulting fees, honoraria, and research funding from AstraZeneca, Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi Sankyo, Janssen, Milestone, Novartis, Merck, Portola, Sanofi, Menarini, Guidotti, and Roche, outside the submitted work. P.K. receives research support for basic, translational, and clinical research projects from European Union Big-Data@Heart (grant agreement EU IMI 116 074), CATCH ME (grant agreement ID: 633 196), and AFFECT-EU (grant agreement ID: 847 770); Leducq foundation, Medical Research Council (UK); German Centre for Cardiovascular Research supported by the German Ministry of Education and Research; and from several drug and device companies active in atrial fibrillation and has received honoraria from several such companies in the past but not in the last 3 years. P.K. is listed as inventor on two patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2 015 140 571 and Markers for Atrial Fibrillation WO 2 016 012 783). P.K. is employed as Director of the Department of Cardiology, University Heart and Vascular Centre UKE Hamburg, and Professor of Cardiovascular Medicine (part-time), University of Birmingham, UK. He is a Speaker of the board of AFNET, Germany, and a Board member of the ESC., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Over the past 20 years, there has been a shift from vitamin K antagonists to direct oral anticoagulants (DOACs), which include the thrombin inhibitor dabigatran and the factor Xa inhibitors apixaban, edoxaban, and rivaroxaban. Although DOACs are associated with less serious bleeding than vitamin K antagonists, bleeding still occurs with DOACs, particularly in the elderly and in those with comorbidities. Reversal of the anticoagulant effects of the DOACs may be needed in patients with serious bleeding and in those requiring urgent surgery or intervention. Reversal can be effected with specific agents, such as idarucizumab for dabigatran and andexanet alfa for apixaban, edoxaban, and rivaroxaban, or with non-specific agents, such as prothrombin complex concentrates, activated prothrombin complex concentrate, and recombinant activated factor VII. This paper (i) provides an update on when and how to reverse the DOACs, (ii) describes new reversal agents under development, and (iii) provides a strategic framework for the reversal of the factor XI inhibitors currently under investigation in phase three clinical trials., Competing Interests: Conflict of interest J.W. has received grant funding from the Canadian Institutes of Health Research. He is a consultant for and received honoraria from Bayer, Alnylam, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi-Sankyo, Ionis, Janssen, Merck, Novartis, Pfizer, Regeneron, and Servier. N.v.E has received grant funding from the Dutch Thrombosis Foundation. He has received honoraria from Boehringer Ingelheim. R.d.C. is a consultant for and received honoraria from Bayer, Janssen–BMS, BMS–Pfizer Alliance, Daiichi-Sankyo, Menarini, Milestone, Portola, Guidotti, Novartis, Merck, Roche, and AstraZeneca. He has participated on the Advisory Board for Janssen–BMS., (© 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.)

Aims: Members of the chromogranin family play a role in angiogenesis. One such biologically active peptide, generated through the processing of chromogranin A, is vasostatin-2. This study aimed at assessing the association of serum vasostatin-2 levels with coronary collateral vessels (CCV) in diabetic patients with chronic total occlusions (CTO) and the effects of vasostatin-2 on angiogenesis in diabetic mice with hindlimb or myocardial ischemia., Methods and Results: Serum levels of vasostatin-2 in 452 diabetic CTO patients were evaluated. The status of CCV was categorized according to the Rentrop score. Vasostatin-2 recombinant protein or phosphate-buffered saline were then injected intraperitoneally in diabetic mouse models of hindlimb or myocardial ischemia, followed by laser Doppler imaging and molecular biology examinations. The effects of vasostatin-2 were also ascertained in endothelial cells and macrophages, with mechanisms clarified using ribonucleic acid (RNA) sequencing. Serum levels of vasostatin-2 were significantly different and progressively higher across Rentrop score 0, 1, 2, and 3 groups (P < .001), with significantly lower levels in patients with poor CCV (Rentrop score 0 and 1) than in those with good CCV (Rentrop score 2 and 3) (P < .05). Vasostatin-2 significantly promoted angiogenesis in diabetic mice with hindlimb or myocardial ischemia. RNA-seq analyzes verified an angiotensin-converting enzyme 2 (ACE2)-mediated vasostatin-2-induction of angiogenesis in ischemic tissues., Conclusion: Lower serum levels of vasostatin-2 are associated with poor CCV in diabetic CTO patients compared with patients with good CCV. Vasostatin-2 significantly promotes angiogenesis in diabetic mice with hindlimb or myocardial ischemia. Such effects are mediated by ACE2., Competing Interests: Conflict of Interest Statement All authors declare no conflict of interest for this contribution., (© 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.)

Haemostasis and thrombosis are closely linked, so that any anticoagulant strategy available today that reduces the thrombotic risk inevitably increases the bleeding risk. However, epidemiological and experimental evidence suggests that inhibiting the contact pathway-the first phase of the intrinsic coagulation pathway-and especially factor XI (FXI) achieves the objective of preventing thrombosis with minimal interference on the haemostatic process. Several pharmacological strategies that act by inhibiting FXI are being studied in clinical trials. Specifically, Phase 2 clinical trials in patients undergoing major orthopaedic surgery, end-stage renal disease, atrial fibrillation (AF), and acute coronary syndrome have shown promising results, allowing clinical research to advance into Phase 3 clinical trials. FXI inhibitors will not necessarily replace currently available direct oral anticoagulants: this would appear too ambitious as of today. However, it is possible to hypothesize that FXI inhibitors are a useful addition to our therapeutic armamentarium in contexts where current anticoagulants have failed or have not been adequately tested, as well as in categories of patients who are at a high risk of bleeding even with current direct oral anticoagulants., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Chronic limb-threatening ischaemia (CLTI) entails dismal outcomes and is an absolute indication to lower extremity revascularization (LER) whenever possible. Antithrombotic therapy is here crucial, but available evidence on best strategies (choice of drugs, combinations, duration) is scarce. We conducted a European internet-based survey on physicians' use of antithrombotic therapy after revascularization for CLTI, under the aegis of the ESC Working Group on Aorta and Peripheral Vascular Disease in collaboration with other European scientific societies involved in CLTI management and agreeing to send the survey to their affiliates., Methods and Results: 225 respondents completed the questionnaire. Antithrombotic therapy following surgical/endovascular LER varies widely across countries and specialties, with dedicated protocols reported only by a minority (36%) of respondents. Dual antiplatelet therapy with aspirin and clopidogrel is the preferred choice for surgical (37%) and endovascular (79%) LER. Dual pathway inhibition (DPI) with aspirin and low-dose rivaroxaban is prescribed by 16% of respondents and is tightly related to the availability of reimbursement (OR 6.88; 95% CI 2.60-18.25) and to the choice of clinicians rather than of physicians performing revascularization (OR 2.69; 95% CI 1.10-6.58). A ≥ 6 months-duration of an intense (two-drug) postprocedural antithrombotic regimen is more common among surgeons than among medical specialists (OR 2.08; 95% CI 1.10-3.94). Bleeding risk assessment is not standardised and likely underestimated., Conclusion: Current antithrombotic therapy of CLTI patients undergoing LER remains largely discretional, and prescription of DPI is related to reimbursement policies. An individualised assessment of thrombotic and bleeding risks is largely missing., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In chronic kidney disease (CKD) patients, hypofiltration may lead to the accumulation of drugs that are cleared mainly by the kidney and, vice versa, hyperfiltration may cause augmented renal excretion of the same drugs. In this review we mainly focus on the issue of whether hyperfiltration significantly impacts the renal clearance of drugs and whether the same alteration may demand an up-titration of the doses applied in clinical practice. About half of severely ill, septic patients and patients with burns show glomerular hyperfiltration and this may lead to enhanced removal of drugs such as hydrophilic antibiotics and a higher risk of antibiotic treatment failure. In general, hyperfiltering obese individuals show higher absolute drug clearances than non-obese control subjects, but this depends on the body size descriptor adopted to adjust for fat excess. Several mechanisms influence pharmacokinetics in type 2 diabetes, including renal hyperfiltration, reduced tubular reabsorption and augmented tubular excretion. However, no consistent pharmacokinetic alteration has been identified in hyperfiltering obese subjects and type 2 diabetics. Non-vitamin K antagonist oral anticoagulants (NOACs) have exhibited lower plasma concentrations in hyperfiltering patients in some studies in patients with atrial fibrillation, but a recent systematic review failed to document any excess risk for stroke and systemic embolism in these patients. Hyperfiltration is common among severely ill patients in intensive care units and drug levels should be measured whenever possible in these high-risk patients to prevent underdosing and treatment failure. Hyperfiltration is also common in patients with obesity or type 2 diabetes, but no consistent pharmacokinetic alteration has been described in these patients. No NOAC dose adjustment is indicated in patients with atrial fibrillation being treated with these drugs., Competing Interests: C.Z. is a Fresenius Medical Care (FMC) Europe consultant and received a fee for lecturing at FMC Israel. C.Z. and F.M. are members of the CKJ editorial board. R.D.C. reports grants from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb–Pfizer alliance, Daiichi-Sankyo, Menarini, Roche, Novartis, Sanofi, Merck, Portola, AstraZeneca, Amgen and Guidotti, all outside the submitted work., (© The Author(s) 2023. Published by Oxford University Press on behalf of the ERA.)

Anticoagulants are the cornerstone for prevention and treatment of thrombosis but are not completely effective, and concerns about the risk of bleeding continue to limit their uptake. Animal studies and experience from patients with genetic coagulation factor XI deficiency suggesting that this factor is more important for thrombosis than for haemostasis raises the potential for drugs that target factor XI to provide safer anticoagulation. Multiple factor XI inhibitors are currently under evaluation in clinical trials, including parenterally administered antisense oligonucleotides, monoclonal antibodies, and orally active small-molecule inhibitors. Promising results of phase 2 trials in patients undergoing major orthopaedic surgery, and in those with end-stage kidney disease, atrial fibrillation and acute coronary syndromes have led to large phase 3 trials that are currently ongoing. We here review premises for the use of these agents, results so far accrued, ongoing studies, and perspectives for future patient care., (© 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.)

Competing Interests: Conflicts of interest: A.H. and C.Z. have no disclosures. R.P.G. declares the following: Institutional research grant to the TIMI Study Group at Brigham and Women’s Hospital from Anthos and Daiichi Sankyo; Honoraria for Lecture/CME programmes from Daiichi Sankyo, Medical Education Resources, Menarini, Merck, Pfizer, SAJA, Servier, Shanghai Medical Telescope; Consultant fees from AstraZeneca, CryoLife, Daiichi Sankyo, Hengrui, Janssen, Pfizer, and Samsung. R.P.G. is a member of the TIMI Study Group which has received institutional research grant support through Brigham and Women’s Hospital from AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc., Merck, Novartis, Pfizer, The Medicines Company. R.D.C. reports grants from Boehringer Ingelheim, Bayer, BMS/Pfizer Alliance, Daiichi Sankyo, Menarini, Roche, Novartis, Sanofi, Merck, Portola, AstraZeneca, Amgen and Guidotti, all outside the submitted work.

Aims: Patients with atrial fibrillation (AF) treated with oral anticoagulation still suffer from cardiovascular complications including cardiovascular death, stroke, and major bleeding. To identify risk factors for predicting stroke and bleeding outcomes in anticoagulated patients, we assessed 2-year outcomes in patients with AF treated with edoxaban in routine care. We also report the age-adjusted risk predictors of clinical outcomes., Methods and Results: The Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular Atrial Fibrillation (ETNA-AF) Europe (NCT02944019) is a prospective, multi-centre, post-authorisation, observational study with an overall 4-year follow-up conducted in 825 centres enrolling edoxaban-treated patients in 10 European countries. Of the 13 133 patients with AF (mean age: 73.6 ± 9.5 years), 5682 (43.3%) were female. At the 2-year follow-up, 9017/13 133 patients were still on edoxaban; 1830 discontinued treatment including 937 who died (annualised event rate of all-cause death was 3.87%). 518 (2.14%) patients died of cardiovascular causes; 234 (0.97%) experienced major bleeding and 168 (0.70%) experienced stroke or systemic embolic events (SEE). Intracranial haemorrhage was noted in 49 patients (0.20%). History of transient ischaemic attack (TIA) at baseline was the strongest predictor of ischaemic stroke or SEE (Wald χ2: 73.63; P < 0.0001). Low kidney function at baseline was the strongest predictor of major bleeding (Wald χ2: 30.68; P < 0.0001). History of heart failure (HF) was the strongest predictor of all-cause (Wald χ2: 146.99; P < 0.0001) and cardiovascular death (Wald χ2: 100.38; P < 0.0001)., Conclusion: Patients treated with edoxaban in ETNA-AF-Europe reported low 2-year event rates in unselected AF patients. Prior stroke, reduced kidney function, and HF identify patients at high risk of stroke, bleeding and all-cause/cardiovascular death, respectively., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Air pollutants are a complex mixture of gaseous substances and particulate matter (PM). Each component potentially has specific harmful effects on human health, but several experimental and clinical studies have shown a strong impact of fine particles on major adverse cardiovascular events. Most of the available evidence concerns the effects of exposure to PM with a diameter of <2.5 µm (PM2.5) and the risk of developing coronary heart disease through inflammation and oxidative stress. While prolonged exposure to PM2.5 has been shown to be associated with the development of atherosclerosis and cardio-metabolic risk factors, short-term exposure has instead proved to be a trigger for acute coronary events, and especially in subjects with pre-existing coronary artery disease. As such, environmental PM2.5 is a major risk element for global public health. This underlines on the one hand not only the need to adopt and encourage preventive measures especially for individuals with a higher risk profile but also to practice environmental policies that are effective in promoting the reduction of exposure to pollutants., Competing Interests: Conflict of interest: None declared., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Frailty is common in patients with atrial fibrillation (AF), with possible impact on therapies and outcomes. However, definitions of frailty are variable, and may not overlap with frailty perception among physicians. We evaluated the prevalence of frailty as perceived by enrolling physicians in the Edoxaban Treatment in Routine Clinical Practice for Patients With Non-Valvular AF (ETNA-AF)-Europe registry (NCT02944019), and compared it with an objective frailty assessment., Methods and Results: ETNA-AF-Europe is a prospective, multi-centre, post-authorization, observational study. There we assessed the presence of frailty according to (i) a binary subjective investigators' judgement and (ii) an objective measure, the Modified Frailty Index. Baseline data on frailty were available in 13 621/13 980 patients. Prevalence of perceived frailty was 10.6%, with high variability among participating countries and healthcare settings (range 5.9-19.6%). Conversely, only 5.0% of patients had objective frailty, with minimal variability (range 4.5-6.7%); and only <1% of patients were identified as frail by both approaches. Compared with non-frailty-perceived, perceived frail patients were older, more frequently female, and with lower body weight; conversely, objectively frail patients had more comorbidities. Non-recommended edoxaban dose regimens were more frequently prescribed in both frail patient categories., Conclusions: Physicians' perception of frailty in AF patients is variable, mainly driven by age, sex, and weight, and quite different compared with the results of an objective frailty assessment. Whatever the approach, frailty appears to be associated with non-recommended anticoagulant dosages. Whether this apparent inappropriateness influences hard outcomes remains to be assessed., Competing Interests: Conflict of interest: I.D. reports having received speaker fees from Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Medtronic, Boston Scientific, and Biotronik. A.B. reports being involved in research sponsored by and is a member of advisory panels and speakers’ bureau for Daiichi Sankyo, Pfizer, BMS, Bayer, and Boehringer Ingelheim. P.-E.R., M.C.M., and J.A.G.d.S. are employees of Daiichi Sankyo Europe GmbH. L.P. has received fees and honoraria from Daiichi-Sankyo, SOTIO Biotech, and Beckman-Coulter. P.K. receives research support from European Union, British Heart Foundation, Leducq Foundation, Medical Research Council (UK), and German Centre for Cardiovascular Research, from several drug and device companies active in atrial fibrillation, and has received honoraria from several such companies. He is listed as inventor on two patents held by the University of Birmingham (Atrial Fibrillation Therapy WO 2015140571, Markers for Atrial Fibrillation WO 2016012783). He is co-principal investigator of ETNA-AF-Europe. R.D.C. co-authored ESC Guidelines on Atrial Fibrillation 2010–2012; acted as a Steering Committee member and National Coordinator for Italy, and co-authored manuscripts published on APPRAISE-2, ARISTOTLE, AVERROES, ENGAGE AF-TIMI 48, and Re-DUAL PCI. R.D.C. has received fees, honoraria, and research funding from Sanofi-Aventis, Boehringer Ingelheim, Bayer, Bristol-Myers Squibb/Pfizer, Daiichi-Sankyo, Novartis, Portola, Roche, and Merck. He is co-principal investigator of ETNA-AF-Europe. All remaining authors have declared no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Thrombolysis is an alternative to surgery for mechanical prosthetic valve thrombosis (MPVT). Randomized clinical trials have yet to test the safety and efficacy of a proposed ultraslow thrombolytic infusion regimen., Methods and Results: This single-centre, open-label, pilot randomized clinical trial randomized adult patients with acute obstructive MPVT to an ultraslow thrombolytic regimen [25 mg of recombinant tissue-type plasminogen activator (rtPA) infused in 25 h] and a fast thrombolytic regimen (50 mg of rtPA infused in 6 h). If thrombolysis failed, a repeated dose of 25 mg of rtPA for 6 h was administered in both groups up to a cumulative dose of 150 mg or the occurrence of a complication. The primary outcome was a complete MPVT resolution (&gt;75% fall in the obstructive gradient by transthoracic echocardiography, &lt;10° limitation in opening and closing valve motion angles by fluoroscopy, and symptom improvement). The key safety outcome was a Bleeding Academic Research Consortium type III or V major bleeding. Overall, 120 patients, including 63 (52.5%) women, at a mean age of 36.3 ± 15.3 years, were randomized. Complete thrombolysis success was achieved in 51 patients (85.0%) in the ultraslow-regimen group and 47 patients (78.3%) in the fast-regimen group [odds ratio 1.58; 95% confidence interval (CI) 0.25-1.63; P = 0.34]. One case of transient ischaemic attack and three cases of intracranial haemorrhage (absolute risk difference -6.6%; 95%CI -12% -0.3%; P = 0.07) were observed only in the fast-regimen group., Conclusion: The ultraslow thrombolytic regimen conferred a high thrombosis resolution rate without major complications. Such findings should be replicated in more adequately powered trials., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

In September 2020, the new Editors of the European Heart Journal (EHJ) wrote the following in their inaugural editorial: "The fundamental mission of the Journal remains the reduction of the global burden of cardiovascular disease. We aspire to advance this aim by worldwide teamwork to communicate practice-changing research, inspire clinical cardiologists, and pursue rigour and transparency in the application of science at the service of human health. The Journal will strive to lead the field in its impact, influence, and reach". After more than one year of experience the Editors hope the cardiological community will agree that they are fulfilling this mission. As stewards of the EHJ, the Editor's primary goal is not solely to achieve a high Impact Factor (which attests to the scientific quality and influence of our publications) but also to elevate the practice of cardiovascular medicine worldwide. Accordingly, various initiatives of the EHJ strive to strengthen further links among Editors, Authors, Reviewers and Readers through a series of coordinated and diverse activities, including webinars, active social media presence, and active participation at congresses worldwide. The Editors are proud to serve one of the most important scientific journals in cardiovascular medicine., (© 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.)

Endothelial progenitor cells (EPCs) are a heterogeneous group of cells present in peripheral blood at various stages of endothelial differentiation. EPCs have been extensively investigated in patients with coronary artery disease (CAD), with controversial findings both on their role in atherosclerosis progression and in the process of neointimal growth after a percutaneous coronary intervention (PCI). Despite nearly 2 decades of experimental and clinical investigations, however, the significance of EPCs in clinical practice remains unclear and poorly understood. This review provides an update on the role of EPCs in the most common clinical scenarios that are experienced by cardiologists managing patients with CAD. We here summarize the main findings on the association of EPCs with cardiovascular risk factors, coronary atherosclerosis, and myocardial ischemia. We then discuss the potential effects of EPCs in post-PCI in-stent restenosis, as well as most recent findings with EPC-coated stents. Based on the mounting evidence of the relationship between levels of EPCs and several different adverse cardiovascular events, EPCs are emerging as novel predictive biomarkers of long-term outcomes in patients with CAD., (© The Author(s) 2022. Published by Oxford University Press.)

Aims: Whether diabetes without insulin therapy is an independent cardiovascular (CV) risk factor in atrial fibrillation (AF) has recently been questioned. We investigated the prognostic relevance of diabetes with or without insulin treatment in patients in the ARISTOTLE trial., Methods and Results: Patients with AF and increased stroke risk randomized to apixaban vs. warfarin were classified according to diabetes status: no diabetes; diabetes on no diabetes medications; diabetes on non-insulin antidiabetic drugs only; or insulin-treated. The associations between such patient subgroups and stroke/systemic embolism (SE), myocardial infarction (MI), and CV death were examined by Cox proportional hazard regression, both unadjusted and adjusted for other prognostic variables. Patients with diabetes were younger and had a higher body mass index. Median CHA2DS2VASc score was 4.0 in patients with diabetes and 3.0 in patients without diabetes. We found no significant difference in stroke/SE incidence across patient subgroups. Compared with no diabetes, only insulin-treated diabetes was significantly associated with higher risk. When adjusted for clinical variables, compared with no diabetes, the hazard ratios (HRs) for MI (95% confidence intervals) were for diabetes on no medication: 1.15 (0.62-2.14); for diabetes on non-insulin antidiabetic drugs: 1.32 (0.90-1.94); for insulin-treated diabetes: 2.34 (1.43-3.82); interaction P = 0.008. HRs for CV death were for diabetes on no medication: 1.19 (0.86-166); for diabetes on non-insulin antidiabetic drugs: 1.12 (0.88-1.42); for insulin-treated diabetes 1.85 (1.36-2.53), interaction P = 0.001., Conclusion: In anticoagulated patients with AF, a higher risk of MI and CV death is largely confined to diabetes treated with insulin., (© The Author(s) 2020. Published on behalf of the European Society of Cardiology.)

Inflammation contributes centrally to cardiovascular diseases, and anti-inflammatory treatments can reduce cardiovascular events. The JAK-STAT pathway is an emerging target in inflammation, mainly in rheumatoid arthritis (RA) and chronic myeloproliferative neoplasms (MPNs), disorders that heighten cardiovascular risk. The aim of this study was to review the international literature on the relationship between dysregulation of the JAK-STAT pathway in RA/MPNs and cardiovascular risk and on the potential cardiovascular effects of JAK-STAT inhibitors. The JAK-STAT pathway sustains inflammatory and thrombotic events in autoimmune disorders such as RA and MPNs. Here, an imbalance exists between pro- and anti-inflammatory cytokines [increased levels of interleukin (IL)-6, IL-1-β, tumour necrosis factor-α, decreased levels of IL-10] and the over-expression of some prothrombotic proteins, such as protein kinase Cε, on the surface of activated platelets. This pathway also operates in atherosclerotic cardiovascular disease. JAK-STAT inhibitors may reduce cardiovascular events and related deaths in such conditions, but the potential of these agents requires more studies, especially with regard to cardiovascular safety, and particularly for potential prothrombotic effects. JAK-STAT inhibitors merit consideration to curb heightened cardiovascular risk in patients with RA and MPNs, with rigorous assessment of the potential benefits and risks., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

The most recent high-sensitivity assays for troponins I and T (hs-TnI and hs-TnT) have made it possible to detect blood concentrations up to 10 times lower than previous assays, making troponins detectable even in asymptomatic subjects without manifest cardiovascular disease. For this reason, hs-Tn, initially introduced as markers of myocardial damage in an acute setting, have also become possible markers of subclinical myocardial damage in baseline conditions. In fact, recent evidence suggests that hs-TnT and hs-TnI predict the risk of future cardiovascular events also in the context of primary prevention, and offer incremental information when added to current risk stratification models. The different association highlighted with different outcome measures, such as coronary heart disease, atherosclerotic cardiovascular disease, heart failure, and death from all causes, seems to indicate that the risk observed in asymptomatic subjects with high levels of hs-Tn is an expression of subclinical damage secondary to multiple pathophysiological mechanisms, and not only to atherothrombosis. However, the ability of hs-TnT and hs-TnI (until now used interchangeably), to provide differential predictive information, and not redundant with respect to more traditional factors, remains to be definitively clarified, both for the purpose of predicting specific outcomes and for the implementation of specific preventive strategies. To date, evidences available allow us to hypothesize their role more as markers than as risk factors., (Published on behalf of the European Society of Cardiology. © The Author(s) 2021.)

A substantial number of chronic coronary syndrome (CCS) patients undergoing percutaneous coronary intervention (PCI) experience periprocedural myocardial injury or infarction. Accurate diagnosis of these PCI-related complications is required to guide further management given that their occurrence may be associated with increased risk of major adverse cardiac events (MACE). Due to lack of scientific data, the cut-off thresholds of post-PCI cardiac troponin (cTn) elevation used for defining periprocedural myocardial injury and infarction, have been selected based on expert consensus opinions, and their prognostic relevance remains unclear. In this Consensus Document from the ESC Working Group on Cellular Biology of the Heart and European Association of Percutaneous Cardiovascular Interventions (EAPCI), we recommend, whenever possible, the measurement of baseline (pre-PCI) cTn and post-PCI cTn values in all CCS patients undergoing PCI. We confirm the prognostic relevance of the post-PCI cTn elevation >5× 99th percentile URL threshold used to define type 4a myocardial infarction (MI). In the absence of periprocedural angiographic flow-limiting complications or electrocardiogram (ECG) and imaging evidence of new myocardial ischaemia, we propose the same post-PCI cTn cut-off threshold (>5× 99th percentile URL) be used to define prognostically relevant 'major' periprocedural myocardial injury. As both type 4a MI and major periprocedural myocardial injury are strong independent predictors of all-cause mortality at 1 year post-PCI, they may be used as quality metrics and surrogate endpoints for clinical trials. Further research is needed to evaluate treatment strategies for reducing the risk of major periprocedural myocardial injury, type 4a MI, and MACE in CCS patients undergoing PCI., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aims: Non-vitamin K oral anticoagulants are safe and effective for stroke prevention in patients with atrial fibrillation (AF). Data on the safety and efficacy of edoxaban in routine care are limited in Europe. We report 1-year outcomes in patients with AF treated with edoxaban in routine care., Methods and Results: ETNA-AF-Europe is a prospective, multicentre, post-authorization, observational study enrolling patients treated with edoxaban in 10 European countries, the design of which was agreed with the European Medicines Agency as part of edoxaban's post-approval safety plan. Altogether 13 092 patients in 852 sites completed the 1-year follow-up [mean age: 73.6 ± 9.5 years; 57% male, mean follow-up: 352 ± 49 days (median: 366 days)]. Most patients had associated comorbidities (mean CHA2DS2-VASc score: 3.1 ± 1.4). Stroke or systemic embolism was reported in 103 patients (annualized event rate: 0.82%/year), and major bleeding events were reported in 132 patients (1.05%/year). Rates of intracranial haemorrhage were low [30 patients (0.24%/year)]. Death occurred in 442 patients (3.50%/year); cardiovascular (CV) death occurred in 206 patients (1.63%/year). The approved dosing of edoxaban was chosen in 83%. All-cause and CV mortality were higher in patients receiving edoxaban 30 mg vs. 60 mg, in line with the higher age and more frequent comorbidities of the 30 mg group. Major bleeding was also numerically more common in patients receiving edoxaban 30 mg vs. 60 mg., Conclusion: The rates of stroke, systemic embolism, and major bleeding are low in this large unselected cohort of high-risk AF patients routinely treated with edoxaban., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: A systemic coagulation dysfunction has been associated with COVID-19. In this case report, we describe a COVID-19-positive patient with multisite arterial thrombosis, presenting with acute limb ischaemia and concomitant ST-elevation myocardial infarction and oligo-symptomatic lung disease., Case Summary: An 83-year-old lady with history of hypertension and chronic kidney disease presented to the Emergency Department with acute-onset left leg pain, pulselessness, and partial loss of motor function. Acute limb ischaemia was diagnosed. At the same time, a routine ECG showed ST-segment elevation, diagnostic for inferior myocardial infarction. On admission, a nasopharyngeal swab was performed to assess the presence of SARS-CoV-2, as per hospital protocol during the current COVID-19 pandemic. A total-body CT angiography was performed to investigate the cause of acute limb ischaemia and to rule out aortic dissection; the examination showed a total occlusion of the left common iliac artery and a non-obstructive thrombosis of a subsegmental pulmonary artery branch in the right basal lobe. Lung CT scan confirmed a typical pattern of interstitial COVID-19 pneumonia. Coronary angiography showed a thrombotic occlusion of the proximal segment of the right coronary artery. Percutaneous coronary intervention was performed, with manual thrombectomy, followed by deployment of two stents. The patient was subsequently transferred to the operating room, where a Fogarty thrombectomy was performed. The patient was then admitted to the COVID area of our hospital. Seven hours later, the swab returned positive for COVID-19., Discussion: COVID-19 can have an atypical presentation with thrombosis at multiple sites., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Despite optimal medical therapies, there is currently a persistent residual cardiovascular risk. The most likely pathway responsible for this residual risk has been identified in the inflammatory state. Recent studies have confirmed that inflammation increases cardiovascular risk independently from LDL cholesterol levels. Addressing traditional risk factors, such as obesity, cigarette smoking, diabetes, arterial hypertension, and dyslipidaemia, also provides an important reduction of the levels of inflammation. Nonetheless, inflammation is also a target for specific and focused therapeutic interventions. Recent studies have outlined an association between oral hygiene, sleep deprivation, and nutritional patterns on the one hand, with the development of multi-districts atherosclerosis and/or adverse cardiovascular events on the other. These lifestyle patterns appear to be involved in fostering inflammation associated with atherosclerosis. There is, however, a persistent need for further studies to clarify whether such associations with cardiovascular disease are direct and causal, and if they are all channelled through vascular inflammation., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Presently several evidences support an association between acute myocardial infarction and influenza infection. The pathophysiology rationale rests on the release of inflammation cytokines, rupture of atherosclerotic plaque, and triggering of prothrombotic events leading to coronary artery occlusion. Several observational evidences support a potential role of influenza vaccine in cardiovascular prevention. It is estimated that the efficacy of influenza vaccine in preventing myocardial infarction could range between 15% and 45%. Notwithstanding the clear recommendation of numerous guidelines concerning patients with cardiovascular diseases, vaccination rates are still low in the high-risk groups. Influenza vaccine as preventive measure of cardiovascular disease still awaits support from randomized clinical trials. Nonetheless, considering the favourable cost-efficacy and safety profile of influenza vaccination, its use should be encouraged in everyday clinical practice., (Published on behalf of the European Society of Cardiology. © The Author(s) 2020.)

Aims: ENSURE-AF (NCT02072434) was the largest prospective randomized clinical trial of anticoagulation for cardioversion in atrial fibrillation (AF), which also provides the largest prospective dataset for transoesophageal echocardiography (TOE) prior to cardioversion. This ancillary analysis investigated determinants of TOE-detected left atrium thrombi (LAT) in patients scheduled for electrical cardioversion (ECV)., Methods and Results: The ENSURE-AF multicentre PROBE evaluation trial compared edoxaban 60 mg once daily (QD) with enoxaparin/warfarin in 2199 subjects undergoing ECV of non-valvular AF. Patients were stratified by the use of TOE, anticoagulant experience, and selected edoxaban dose. Electrical cardioversion was cancelled or deferred when TOEdetected LAT. In total, 1183 subjects were stratified to the TOE arm and LAT was reported in 91 (8.2%). In univariate analysis, age ≥75 years (26.4% vs. 16.9%, P = 0.0308), lower weight (86.5 ± 15.0 vs. 90.7 ± 18.0 kg, P = 0.0309), lower creatinine clearance (80.1 ± 30.6 vs. 93.2 ± 33.9 mL/min, P = 0.0007), heart failure (59.3% vs. 43.0%, P = 0.0029), and diuretic treatment (53.9% vs. 40.1%, P = 0.0141) were more prevalent in the LAT group. Non-significant trends were seen for higher mean CHA2DS2-VASc score (3.0 ± 1.41 vs. 2.7 ± 1.48, P = 0.0571) and more prevalent anticoagulation use prior to enrolment (60.4% vs. 50.3%, P = 0.0795) in the LAT group. In logistic regression analysis, age (P = 0.0202) and heart failure (P = 0.0064) were independently associated with LAT., Conclusion: Elective ECV is commonly cancelled or deferred due to TOE-detected LAT in patients with non-valvular AF. Age ≥75 years and heart failure were associated with the presence of LAT., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.)