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The term early repolarization has been in use for more than 50 years. This electrocardiographic pattern was considered benign until 2008, when it was linked to sudden cardiac arrest due to idiopathic ventricular fibrillation. Much confusion over the definition of early repolarization followed. Thus, the objective of this paper was to prepare an agreed definition to facilitate future research in this area. The different definitions of the early repolarization pattern were reviewed to delineate the electrocardiographic measures to be used when defining this pattern. An agreed definition has been established, which requires the peak of an end-QRS notch and/or the onset of an end-QRS slur as a measure, denoted Jp, to be determined when an interpretation of early repolarization is being considered. One condition for early repolarization to be present is Jp ≥0.1 mV, while ST-segment elevation is not a required criterion., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Although the use of oral anticoagulants (vitamin K antagonists) has been abandoned in primary cardiovascular prevention due to lack of a favorable benefit-to-risk ratio, the indications for aspirin use in this setting continue to be a source of major debate, with major international guidelines providing conflicting recommendations. Here, we review the evidence in favor and against aspirin therapy in primary prevention based on the evidence accumulated so far, including recent data linking aspirin with cancer protection. While awaiting the results of several ongoing studies, we argue for a pragmatic approach to using low-dose aspirin in primary cardiovascular prevention and suggest its use in patients at high cardiovascular risk, defined as ≥2 major cardiovascular events (death, myocardial infarction, or stroke) projected per 100 person-years, who are not at increased risk of bleeding., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Until recently, vitamin K antagonists were the only available oral anticoagulants, but with numerous limitations that prompted the introduction of new oral anticoagulants targeting the single coagulation enzymes thrombin (dabigatran) or factor Xa (apixaban, rivaroxaban, and edoxaban) and given in fixed doses without coagulation monitoring. Here we review the pharmacology and the results of clinical trials with these new agents in stroke prevention in atrial fibrillation and secondary prevention after acute coronary syndromes, providing perspectives on their future incorporation into clinical practice. In phase III trials in atrial fibrillation, compared with warfarin, dabigatran etexilate 150 mg B.I.D. reduced the rates of stroke/systemic embolism without any difference in major bleeding; dabigatran etexilate 110 mg B.I.D. had similar efficacy with decreased bleeding; apixaban 5 mg B.I.D. reduced stroke, systemic embolism, and mortality as well as major bleeding; and rivaroxaban 20 mg Q.D. was noninferior to warfarin for stroke and systemic embolism without a difference in major bleeding. All these agents reduced intracranial hemorrhage. Edoxaban is currently being evaluated in a further large phase III trial. Apixaban and rivaroxaban were evaluated in phase III trials for prevention of recurrent ischemia in patients with acute coronary syndromes who were mostly receiving dual antiplatelet therapy, with conflicting results on efficacy but consistent results for increased major bleeding. Overall, the new oral anticoagulants are poised to replace vitamin K antagonists for many patients with atrial fibrillation and may have a role after acute coronary syndromes. Although convenient to administer and manage, they present challenges that need to be addressed., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiovascular magnetic resonance (CMR) has become the primary tool for noninvasive assessment of myocardial inflammation in patients with suspected myocarditis. The International Consensus Group on CMR Diagnosis of Myocarditis was founded in 2006 to achieve consensus among CMR experts and develop recommendations on the current state-of-the-art use of CMR for myocarditis. The recommendations include indications for CMR in patients with suspected myocarditis, CMR protocol standards, terminology for reporting CMR findings, and diagnostic CMR criteria for myocarditis (i.e., "Lake Louise Criteria").

Cardiac remodeling is generally accepted as a determinant of the clinical course of heart failure (HF). Defined as genome expression resulting in molecular, cellular and interstitial changes and manifested clinically as changes in size, shape and function of the heart resulting from cardiac load or injury, cardiac remodeling is influenced by hemodynamic load, neurohormonal activation and other factors still under investigation. Although patients with major remodeling demonstrate progressive worsening of cardiac function, slowing or reversing remodeling has only recently become a goal of HF therapy. Mechanisms other than remodeling can also influence the course of heart disease, and disease progression may occur in other ways in the absence of cardiac remodeling. Left ventricular end-diastolic and end-systolic volume and ejection fraction data provide support for the beneficial effects of therapeutic agents such as angiotensin-converting enzyme (ACE) inhibitors and beta-adrenergic blocking agents on the remodeling process. These agents also provide benefits in terms of morbidity and mortality. Although measurement of ejection fraction can reliably guide initiation of treatment in HF, opinions differ regarding the value of ejection fraction data in guiding ongoing therapy. The role of echocardiography or radionuclide imaging in the management and monitoring of HF is as yet unclear. To fully appreciate the potential benefits of HF therapies, clinicians should understand the relationship between remodeling and HF progression. Their patients may then, in turn, acquire an improved understanding of their disease and the treatments they are given.

Statins are the most common drugs administered for patients with cardiovascular disease. However, due to statin-associated muscle symptoms, adherence to statin therapy is challenging in clinical practice. Certain nutraceuticals, such as red yeast rice, bergamot, berberine, artichoke, soluble fiber, and plant sterols and stanols alone or in combination with each other, as well as with ezetimibe, might be considered as an alternative or add-on therapy to statins, although there is still insufficient evidence available with respect to long-term safety and effectiveness on cardiovascular disease prevention and treatment. These nutraceuticals could exert significant lipid-lowering activity and might present multiple non-lipid-lowering actions, including improvement of endothelial dysfunction and arterial stiffness, as well as anti-inflammatory and antioxidative properties. The aim of this expert opinion paper is to provide the first attempt at recommendation on the management of statin intolerance through the use of nutraceuticals with particular attention on those with effective low-density lipoprotein cholesterol reduction., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

The historical origin of the term "lone atrial fibrillation" (AF) predates by 60 years our current understanding of the pathophysiology of AF, the multitude of known etiologies for AF, and our ability to image and diagnose heart disease. The term was meant to indicate AF in patients for whom subsequent investigations could not demonstrate heart disease, but for many practitioners has become synonymous with "idiopathic AF." As the list of heart diseases has expanded and diagnostic techniques have improved, the prevalence of lone AF has fallen. The legacy of the intervening years is that definitions of lone AF in the literature are inconsistent so that studies of lone AF are not comparable. Guidelines provide a vague definition of lone AF but do not provide direction about how much or what kind of imaging and other testing are necessary to exclude heart disease. There has been an explosion in the understanding of the pathophysiology of AF in the last 20 years in particular. Nevertheless, there are no apparently unique mechanisms for AF in patients categorized as having lone AF. In addition, the term "lone AF" is not invariably useful in making treatment decisions, and other tools for doing so have been more thoroughly and carefully validated. It is, therefore, recommended that use of the term "lone AF" be avoided., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

For most patients, direct oral anticoagulants (DOACs) are preferred over vitamin K antagonists for stroke prevention in atrial fibrillation and for venous thromboembolism treatment. However, randomized controlled trials suggest that DOACs may not be as efficacious or as safe as the current standard of care in conditions such as mechanical heart valves, thrombotic antiphospholipid syndrome, and atrial fibrillation associated with rheumatic heart disease. DOACs do not provide a net benefit in conditions such as embolic stroke of undetermined source. Their efficacy is uncertain for conditions such as left ventricular thrombus, catheter-associated deep vein thrombosis, cerebral venous sinus thrombosis, and for patients with atrial fibrillation or venous thrombosis who have end-stage renal disease. This paper provides an evidence-based review of randomized controlled trials on DOACs, detailing when they have demonstrated efficacy and safety, when DOACs should not be the standard of care, where their safety and efficacy are uncertain, and areas requiring further research., Competing Interests: Funding Support and Author Disclosures Dr Piazza has received research support paid to his institution from Bristol Myers Squibb/Pfizer Alliance, Bayer, Janssen, Alexion, Amgen, and Boston Scientific Corporation; and has received consulting fees from Pfizer, Boston Scientific Corporation, Janssen, and Amgen. Dr Fanikos has served as a consultant to AstraZeneca, Mallinckrodt, and Pfizer. Dr Connors has received research funding to her institution from CSL Behring; has received consulting fees from Abbott; has received honoraria for lectures from Bristol Myers Squibb, Roche, and Sanofi; and has participated on the advisory board of Abbott, Alnylam, Anthos, Bristol Myers Squibb, Sanofi, and Takeda, outside of the submitted work. Dr Siegal is supported by a Tier 2 Canada Research Chair in Anticoagulant Management of Cardiovascular Disease; declares that she has received honoraria paid indirectly to her research institute from AstraZeneca, Bristol Myers Squibb-Pfizer, Roche, and Servier. Dr Barnes has served as a consultant for Pfizer, Bristol Myers Squibb, Janssen, Bayer, AstraZeneca, Sanofi, Anthos, Boston Scientific, and Abbott Vascular; and has received grant funding from Boston Scientific. Dr Martin is supported by National Institutes of Health K23HL157758; and has received research support paid to her institution from Janssen Scientific Affairs. Dr Angiolillo has received consulting fees or honoraria from Abbott, Amgen, AstraZeneca, Bayer, Biosensors, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, CSL Behring, Daiichi-Sankyo, Eli Lilly, Haemonetics, Janssen, Merck, Novartis, PhaseBio, PLx Pharma, Pfizer, Sanofi, and Vectura; and his institution has received research grants from Amgen, AstraZeneca, Bayer, Biosensors, CeloNova, CSL Behring, Daiichi-Sankyo, Eisai, Eli Lilly, Gilead, Idorsia, Janssen, Matsutani Chemical Industry Co, Merck, Novartis, and the Scott R. MacKenzie Foundation. Dr Kleindorfer has received other support from the University of Michigan College of Medicine. Dr Monreal has received unrestricted grants for research from Sanofi, Leo and Rovi; and has participated in advisory meetings sponsored by Sanofi. Dr Jimenez has served as an advisor or consultant for Pfizer and Sanofi; and has served as a speaker or a member of a Speakers Bureau for Bristol Myers Squibb, Pfizer and Sanofi. Dr Middeldorp has received grants and personal fees from Daiichi-Sankyo, Bayer, Pfizer, and Boehringer Ingelheim; and has received personal fees from Portola/Alexion, Abbvie, Pfizer/Bristol Myers Squibb, Norgine, Viatris, and Sanofi, all paid to her institution and outside of the submitted work. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance; has received ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention; and has received royalties from UpToDate for chapters on stroke. Dr Elkind has received study drug in kind from the Bristol Myers Squibb-Pfizer Alliance and ancillary research funding from Roche for a National Institutes of Health-funded trial of stroke prevention, and royalties from UpToDate for chapters on stroke. Dr Ruff is a member of the TIMI Study Group, which has received institutional research grant support through Brigham and Women’s Hospital from Abbott, Amgen, Anthos Therapeutics, ARCA Biopharma, Inc, AstraZeneca, Bayer HealthCare Pharmaceuticals, Inc, Daiichi-Sankyo, Eisai, Intarcia, Ionis Pharmaceuticals, Inc, Janssen Research and Development, LLC, MedImmune, Merck, Novartis, Pfizer, Quark Pharmaceuticals, Regeneron Pharmaceuticals, Inc, Roche, Siemens Healthcare Diagnostics, Inc, Softcell Medical Limited, The Medicines Company, and Zora Biosciences. Dr Goldhaber has received research support from Bayer, Bristol Myers Squibb, Boston Scientific BTG EKOS, Janssen, National Heart, Lung, and Blood Institute, and Pfizer; and has received consulting fees from Agile, Bayer, and Pfizer, outside of the submitted work. In the past 3 years, Dr Krumholz has received expenses and/or personal fees from UnitedHealth, Element Science, Eyedentifeye, and F-Prime; is a co-founder of Refactor Health and HugoHealth; and is associated with contracts, through Yale New Haven Hospital, from the Centers for Medicare and Medicaid Services and through Yale University from Janssen, Google, and Pfizer. Dr Mehran has received institutional research payments from Abbott, Abiomed, Alleviant Medical, Amgen, AM-Pharma, Arena, AstraZeneca, AtriCure Inc, Biosensors, Biotronik, Boston Scientific, Bristol Myers Squibb, CardiaWave, CeloNova, Chiesi, Concept Medical, Cytosorbents, Daiichi-Sankyo, Element Science, Faraday, Humacyte, Idorsia Pharmaceuticals, Janssen, Magenta, MedAlliance, Mediasphere, Medtelligence, Medtronic, MJH Healthcare, Novartis, OrbusNeich, Penumbra, PhaseBio, Philips, Pi-Cardia, PLx Pharma, Protembis, RenalPro, RM Global, Shockwave, Vivasure, Zoll; has received personal fees from Ionis Pharmaceuticals, J-CalC, Novartis, NovoNordisk, Vectura, VoxMedia, WebMD, IQVIA, McVeigh Global, Overcome, Primer Healthcare of New Jersey, Radcliffe, SL Solutions, TARSUS Cardiology, and Esperion Science/Innovative Biopharma; has received honoraria from JAMA Cardiology (Associate Editor) and the ACC (BOT Member, SC Member CTR Program); and has equity <1% in Applied Therapeutics, Elixir Medical, Stel, ControlRad (spouse). Dr Eikelboom has received fees, honoraria and/or research support from Anthos, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, DSI, Janssen, Pfizer, Servier, and Takeda. Dr Lip is a consultant and speaker for Bristol Myers Squibb/Pfizer, Boehringer Ingelheim, Daiichi-Sankyo, and Anthos, no fees are received personally; and is coprincipal investigator of the AFFIRMO project on multimorbidity in AF, which has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement #899871. Dr Weitz has served as a consultant and has received honoraria from Alnylam, Anthos, Bayer, Bristol Myers Squibb, Ionis, Janssen, Merck, Pfizer, Regeneron, and Servier. Dr Lopes reports research grants or contracts from Amgen, Bristol Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi; funding for educational activities or lectures from Pfizer, Bristol Myers Squibb, Novo Nordisk, and AstraZeneca; and has received funding for consulting from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, NovoNordisk, and AstraZeneca. Dr Bikdeli is supported by a Career Development Award from the American Heart Association and VIVA Physicians (#938814); was supported by the Scott Schoen and Nancy Adams IGNITE Award; is supported by the Mary Ann Tynan Research Scientist award from the Mary Horrigan Connors Center for Women’s Health and Gender Biology at Brigham and Women’s Hospital, and the Heart and Vascular Center Junior Faculty Award from Brigham and Women’s Hospital; is a consulting expert, on behalf of the plaintiff, for litigation related to 2 specific brand models of IVC filters; has not been involved in the litigation in 2022 or 2023 nor has he received any compensation in 2022 or 2023; is a member of the Medical Advisory Board for the North American Thrombosis Forum; and serves in the Data Safety and Monitory Board of the NAIL-IT trial funded by the National Heart, Lung, and Blood Institute, and Translational Sciences. All other authors have reported that they have no relationships related to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Optical coherence tomography (OCT) and intravascular ultrasound (IVUS) have shown comparable outcomes in guiding percutaneous coronary intervention (PCI). However, their comparative effectiveness in complex coronary artery lesions remains unclear., Objectives: This study compared the effectiveness and safety of OCT-guided vs IVUS-guided PCI for complex coronary artery lesions., Methods: This was a prespecified, main subgroup analysis of complex coronary artery lesions in the OCTIVUS (Optical Coherence Tomography Versus Intravascular Ultrasound Guided Percutaneous Coronary Intervention) trial, which included unprotected left main disease, bifurcation disease, an aorto-ostial lesion, a chronic total occlusion, a severely calcified lesion, an in-stent restenotic lesion, a diffuse long lesion, or multivessel PCI. The primary endpoint was a composite of death from cardiac causes, target vessel-related myocardial infarction, or ischemia-driven target vessel revascularization., Results: In 2,008 randomized patients, 1,475 (73.5%) underwent imaging-guided PCI for complex coronary artery lesions; 719 (48.7%) received OCT-guided and 756 (51.3%) IVUS-guided PCI. At a median follow-up of 2.0 years, primary endpoint event had occurred in 47 patients (6.5%) in the OCT-guided group and in 56 patients (7.4%) in the IVUS-guided group (HR: 0.87; 95% CI: 0.59-1.29; P = 0.50). These findings were consistent in adjusted analyses. The incidence of contrast-induced nephropathy was similar between the 2 groups (1.9% vs 1.5%; P = 0.46). The incidence of major procedural complications was lower in the OCT-guided group than in the IVUS-guided group (1.7% vs 3.4%; P = 0.03)., Conclusions: Among patients with complex coronary artery lesions, OCT-guided PCI showed a similar risk of primary composite event of death from cardiac causes, target vessel-related myocardial infarction, or target vessel revascularization as compared with IVUS-guided PCI. (Optical Coherence Tomography Versus Intravascular Ultrasound Guided Percutaneous Coronary Intervention [OCTIVUS]; NCT03394079)., Competing Interests: Funding Support and Author Disclosures This study was an investigator-initiated trial and was funded by the CardioVascular Research Foundation, Abbott Vascular, and Medtronic. The funders of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report. Dr S.-J. Park has received research grants or speaker fees from Abbott Vascular, Medtronic, Daiichi-Sankyo, ChongKunDang Pharm, Daewoong Pharm, and Edwards. Dr D.-W. Park has received research grants or speaker fees from Abbott Vascular, Medtronic, and Daiichi-Sankyo; and has received grants from ChongKunDang Pharm and Daewoong Pharm. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Phosphodiesterase-5 inhibitor (PDE5i) treatment for erectile dysfunction is associated with lower mortality compared with no treatment for erectile dysfunction after myocardial infarction (MI). There are conflicting results regarding the impact of PDE5i treatment on mortality in conjunction with nitrate medication., Objectives: The purpose of this study was to investigate the association between PDE5i treatment and cardiovascular outcomes in men with stable coronary artery disease treated with nitrate medication., Methods: Using the Swedish Patient Register and the Prescribed Drug Register we included men with previous MI or revascularization in 2006-2013 who had 2 dispensed nitrate prescriptions within 6 months. Exposure was defined as at least 2 filled prescriptions of any PDE5i. We performed multivariable Cox proportional hazard regression to estimate HRs with 95% CIs for all-cause, cardiovascular, and noncardiovascular mortality, MI, heart failure, cardiac revascularization, and major cardiovascular events (MACE)., Results: In total, 55,777 men were treated with nitrates and 5,710 men with nitrates and a PDE5i. The combined use of PDE5i treatment with nitrates was associated with higher mortality (HR: 1.39; 95% CI: 1.28-1.51), cardiovascular mortality (HR: 1.34; 95% CI: 1.11-1.62), noncardiovascular mortality (HR: 1.40; 95% CI: 1.27-1.54), MI (HR: 1.72; 95% CI: 1.55-1.90), heart failure (HR: 1.67; 95% CI: 1.48-1.90), cardiac revascularization (HR: 1.95; 95% CI: 1.78-2.13), and MACE (HR: 1.70; 95% CI: 1.58-1.83)., Conclusions: The use of a PDE5i in combination with nitrate medication in men with stable coronary artery disease may pose an increased hazard for cardiovascular morbidity and mortality. Careful patient-centered consideration before prescribing PDE5is to patients with cardiovascular disease using nitrate medication is warranted., Competing Interests: Funding Support and Author Disclosures Dr Trolle Lagerros was funded by the Stockholm County Council (clinical research appointment). Dr Andersson was funded by the Stockholm County Council (no. 954970, 963296, 962029), CIMED, and the Strategic Research Program at Karolinska Institutet (no. 961507). None of the funders were involved in the design, conduct of the study, data collection, data analysis, interpretation of data, or preparation, review, or approval of the manuscript. Dr Andersson has received nonfinancial support from COVIS Pharma (study drug donation) as principal investigator in another study; is site principal investigator for Ionis 678354 for Ionis Pharmaceuticals; and is employed at Werlabs; none of these studies or the outside employment are related to the present work. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Evidence is limited regarding patient outcomes comparing redo surgical mitral valve replacement (redo SMVR) vs transcatheter mitral valve replacement (TMVR) for failed prostheses., Objectives: The goal of this study was to compare the outcomes of redo SMVR vs TMVR in patients with failed prostheses, as well as evaluate the association between case volume and outcomes., Methods: Medicare beneficiaries aged ≥65 years who underwent redo SMVR or TMVR for failed mitral prostheses between 2016 and 2020 were included. The primary endpoint was mid-term (up to 3 years) major adverse cardiovascular events (MACE), including all-cause death, heart failure rehospitalization, stroke, or reintervention. Propensity score-matched analysis was used., Results: A total of 4,293 patients were included (redo SMVR: 64%; TMVR: 36%). TMVR recipients were older, with a higher comorbidity burden. In matched cohort (n = 1,317 in each group), mid-term risk of MACE was similar (adjusted HR: 0.92; 95% CI: 0.80-1.04; P = 0.2). However, landmark analysis revealed a lower risk of MACE with TMVR in the first 6 months (adjusted HR: 0.75; 95% CI: 0.63-0.88; P < 0.001) albeit with a higher risk beyond 6 months (adjusted HR: 1.28; 95% CI: 1.04-1.58; P = 0.02). Increasing procedural volume was associated with decreased risk of mid-term MACE after redo SMVR (P = 0.001) but not after TMVR (P = 0.3)., Conclusions: In this large cohort of Medicare beneficiaries with failed mitral prostheses, outcomes were similar between redo SMVR and TMVR at 3 years, with TMVR showing a lower initial risk but a higher risk of MACE after 6 months. These findings highlight the importance of striking a balance between surgical risk, anticipated longevity, and hospital expertise when selecting interventions., Competing Interests: Funding Support and Author Disclosures Dr Latib is a consultant for and on the advisory board of Medtronic, Abbott, Boston Scientific, and Philips. Dr Kaneko has received consulting fees from Edwards Lifesciences, Medtronic, 4C Medical, CardioMech, and Cook Medical; and has been a speaker for Abbott and Baylis. Dr Tsugawa has received grants from the National Institutes of Health/National Institute on Aging (R01AG068633 and R01AG082991), National Institutes of Health/National Institute on Minority Health and Health Disparities (R01MD013913), and Gregory Annenberg Weingarten GRoW @Annenberg outside the submitted work; and has served on the board of directors for M3 Inc. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: There is currently no established recommendation for antithrombotic treatment following transcatheter mitral valve replacement (TMVR). However, based on the analogy with surgical mitral bioprosthesis, vitamin K antagonists (VKAs) are predominantly used., Objectives: The purpose of this study was to compare bleeding and thrombotic events associated with direct oral anticoagulants (DOACs) or VKAs in a prospective cohort of TMVR patients., Methods: We enrolled consecutive patients who underwent transseptal TMVR using a SAPIEN family prosthesis at our center between 2011 and 2023. The primary outcome was the occurrence of bleeding. VKAs were administered to patients until October 2019, after which DOACs were prescribed. The median follow-up was 4.7 months (Q1-Q3: 2.6-6.7 months)., Results: A total of 156 patients were included. The mean age was 65 ± 18.5 years, and 103 patients (66%) were women. The median EuroSCORE II was 7.48% (Q1-Q3: 3.80%-12.97%). Of the participants, 20.5% received DOACs and 79.5% were treated with VKAs. The primary outcome was observed in 50 (40%) patients in the VKA group and 3 (9%) patients in the DOAC group (adjusted HR: 0.21; 95% CI: 0.06-0.74; P = 0.02). Treatment with DOAC was associated with a shorter length of hospital stay. No significant differences were found in terms of thrombotic events, major vascular complications, stroke, or death., Conclusions: The use of DOACs after TMVR, compared with VKAs, appears to reduce the risk of bleeding complications and decrease the length of hospital stay for patients, without a significant increase in the risk of thrombotic events., Competing Interests: Funding Support and Author Disclosures Dr Himbert is a proctor for Edwards Lifesciences and Abbott. Dr Brochet is a proctor for Abbott. Prof Urena has received speaker fees from Edwards Lifesciences and Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Prior studies have demonstrated worse long-term outcomes for women after surgery for severe mitral regurgitation (MR). The current Class I indications for surgery for severe degenerative MR use cutoffs of left ventricular end-systolic dimension (LVESD) and left ventricular ejection fraction (EF) that do not account for known sex-related differences., Objectives: The primary objective of this study was to assess long-term mortality following mitral valve repair in women compared with men on the basis of preoperative left ventricular systolic dimensions and EF., Methods: Consecutive patients who underwent isolated mitral valve repair for degenerative MR at a single institution between 1994 and 2016 were screened. Adjusted HRs for all-cause mortality were compared according to baseline LVESD, LVESD indexed to body surface area (LVESDi), and EF for men and women., Results: Among 4,589 patients, 1,825 were women (40%), and after a median follow-up period of 7.2 years, 344 patients (7.5%) had died. The risk for mortality for women increased from the baseline hazard at an LVESD of 3.6 cm, whereas an inflection point for increased risk with LVESD was not evident in men. Regarding LVESDi, the risk for women increased at 1.8 cm/m 2 compared with 2.1 cm/m 2 in men. For EF, women and men had a similar inflection point (58%); however, mortality was higher for women as EF decreased., Conclusions: After mitral valve repair, women have a higher risk for all-cause mortality at lower LVESD and LVESDi and higher EF. These results support consideration of sex-specific thresholds for LVESDi in surgical decision making for patients with severe MR., Competing Interests: Funding Support and Author Disclosures This work was supported by Women’s Cardiovascular Research at the Cleveland Clinic. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Athletes epitomize the healthiest segment of society. Despite this premise, sudden cardiac death may occur in apparently healthy athletes, attracting significant attention not only in the medical community but also in laypersons and media. The incidence of sudden cardiac death is variably reported, and epidemiological burden differs among cohorts. Athletes appear to be at risk of developing fatal arrhythmias when harboring a quiescent cardiac disorder. Primary cardiomyopathies, ion channelopathies, and coronary artery anomalies are prevalent causes in young individuals. Cardiac assessment of athletes can be challenging because these individuals exhibit a plethora of electrical, structural, and functional physiological changes that overlap with cardiac pathology. A diagnosis of cardiac disease in a young athlete is not necessarily an indication to terminate competition and sports participation. International guidelines, traditionally focused on disqualification of individuals with cardiac disease, have recently adopted a more liberal attitude, based on a careful assessment of the risk and on a shared-decision making approach., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Exercise electrocardiographic stress testing (EST) has historically been validated against the demonstration of obstructive coronary artery disease. However, myocardial ischemia can occur because of coronary microvascular dysfunction (CMD) in the absence of obstructive coronary artery disease., Objectives: The aim of this study was to assess the specificity of EST to detect an ischemic substrate against the reference standard of coronary endothelium-independent and endothelium-dependent microvascular function in patients with angina with nonobstructive coronary arteries (ANOCA)., Methods: Patients with ANOCA underwent invasive coronary physiological assessment using adenosine and acetylcholine. CMD was defined as impaired endothelium-independent and/or endothelium-dependent function. EST was performed using a standard Bruce treadmill protocol, with ischemia defined as the appearance of ≥0.1-mV ST-segment depression 80 ms from the J-point on electrocardiography. The study was powered to detect specificity of ≥91%., Results: A total of 102 patients were enrolled (65% women, mean age 60 ± 8 years). Thirty-two patients developed ischemia (ischemic group) during EST, whereas 70 patients did not (nonischemic group); both groups were phenotypically similar. Ischemia during EST was 100% specific for CMD. Acetylcholine flow reserve was the strongest predictor of ischemia during exercise. Using endothelium-independent and endothelium-dependent microvascular dysfunction as the reference standard, the false positive rate of EST dropped to 0%., Conclusions: In patients with ANOCA, ischemia on EST was highly specific of an underlying ischemic substrate. These findings challenge the traditional belief that EST has a high false positive rate., Competing Interests: Funding Support and Author Disclosures This work is supported by grants from the Medical Research Council (MR/T029390/1), the British Heart Foundation (FS/16/49/32320), and the UK National Institute for Health Research (through the Biomedical Research Center award to King’s College London and Guy’s and St. Thomas’ Hospital). Prof Shah is supported by the British Heart Foundation (CH/1999001/11735). The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Electrophysiological and interventional procedures have been increasingly used to reduce morbidity and mortality in patients experiencing cardiovascular diseases. Although antithrombotic therapies are critical to reduce the risk of stroke or other thromboembolic events, they can nonetheless increase the bleeding hazard. This is even more true in an aging population undergoing cardiac procedures in which the combination of oral anticoagulants and antiplatelet therapies would further increase the hemorrhagic risk. Hence, the timing, dose, and combination of antithrombotic therapies should be carefully chosen in each case. However, the maze of society guidelines and consensus documents published so far have progressively led to a hazier scenario in this setting. Aim of this review is to provide-in a single document-a quick, evidenced-based practical summary of the antithrombotic approaches used in different cardiac electrophysiology and interventional procedures to guide the busy clinician and the cardiac proceduralist in their everyday practice., Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking., Objectives: In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF., Methods: Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment., Results: DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred., Conclusions: The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart., Competing Interests: Funding Support and Author Disclosures This project was supported by H2020-NMBP-2016 720834 CUPIDO to Drs Alogna, Catalucci, de Luca, Iafisco, Guillot, Longinotti-Buitoni, and Post. Dr Alogna is supported by the Clinician Scientist Program of the Berlin Institute of Health, Germany. This work is additionally funded by the Deutsche Forschungsgemeinschaft (German Research Foundation; SFB-1470, Z01). Dr Catalucci is author on patent application no. MI2014A000097 and PCT/EP2015/051376 (WO2015/110589) “Mimetic peptides and their use in medicine” submitted by the Italian National Research Council, which covers MP that, through a novel mechanism, directly target the LTCC and are suitable for use in the treatment of conditions where LTCC density and function are altered. Drs Catalucci and Iafisco are authors on patent application nos. MI2014A002207 and PCT/EP2015/080991 (WO2016/102576), “Products for the delivery of therapeutic/diagnostic compounds to the heart,” submitted by the Italian National Research Council (75%) and the Italian Istituto Nazionale Assicurazione Infortuni sul Lavoro (25%), which cover a process for the preparation of a product comprising 1 or more nanoparticles of CaP that are suitable for use as a vehicle for 1 or more diagnostic/therapeutic compounds for the treatment of CVDs. Drs Colombo, Quarta, Catalucci, and Iafisco are inventors of the patent WO WO2022/053955 “Powder composition based on microparticles embedding nanoparticles for the delivery of therapeutic/diagnostic compounds” submitted by the Italian National Research Council (50%) and PlumeStars (50%), which relates to a powder composition for inhalation use comprising a population of microparticles comprising at least 1 water-soluble pharmaceutical carrier embedding at least one nanoparticle of calcium phosphate for the delivery of therapeutic/diagnostic compounds. Drs de Luca, Catalucci, Iafisco, and Alogna are founders of NanoPhoria, a preclinical-stage biotech company and National Research Council spin-off that is developing a versatile, nonviral drug delivery platform based on inorganic nanoparticles. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent years have witnessed exponential growth in cardiac imaging technologies, allowing better visualization of complex cardiac anatomy and improved assessment of physiology. These advances have become increasingly important as more complex surgical and catheter-based procedures are evolving to address the needs of a growing congenital heart disease population. This state-of-the-art review presents advances in echocardiography, cardiac magnetic resonance, cardiac computed tomography, invasive angiography, 3-dimensional modeling, and digital twin technology. The paper also highlights the integration of artificial intelligence with imaging technology. While some techniques are in their infancy and need further refinement, others have found their way into clinical workflow at well-resourced centers. Studies to evaluate the clinical value and cost-effectiveness of these techniques are needed. For techniques that enhance the value of care for congenital heart disease patients, resources will need to be allocated for education and training to promote widespread implementation., Competing Interests: Funding Support and Author Disclosures Dr Armstrong is a consultant for Edwards Lifesciences, Medtronic, Cook Medical, Abbott, and Starlight Cardiovascular; and receives research support from Siemens Healthineers and Renata Medical. Dr Grosse-Wortmann is a consultant for Siemens Healthineers. Dr Powell is a consultant for Siemens Healthineers. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: In the TRILUMINATE Pivotal (Trial to Evaluate Cardiovascular Outcomes in Patients Treated with the Tricuspid Valve Repair System Pivotal), tricuspid transcatheter edge-to-edge repair (T-TEER) reduced tricuspid regurgitation (TR) and improved health status compared with medical therapy alone with no benefit on heart failure hospitalizations or survival., Objectives: The purpose of this study was to better understand the health status benefits of T-TEER within the TRILUMINATE Pivotal trial., Methods: TRILUMINATE randomized patients with severe TR to T-TEER (n = 175) or medical therapy (n = 175). Health status was assessed at baseline and at 1, 6, and 12 months with the Kansas City Cardiomyopathy Questionnaire (KCCQ) (range 0-100; higher = better), which was compared between treatment groups using mixed effects linear regression. Alive and well was defined as KCCQ overall summary score ≥60 and no decline from baseline of >10 points at 1 year., Results: Compared with medical therapy, T-TEER significantly improved health status at 1 month (mean between-group difference in KCCQ overall summary score 9.4 points; 95% CI: 5.3-13.4 points), with a small additional improvement at 1 year (mean between-group difference 10.4 points; 95% CI: 6.3-14.6 points). T-TEER patients were more likely to be alive and well at 1 year (T-TEER vs medical therapy: 74.8% vs 45.9%; P < 0.001), with a number needed to treat of 3.5. Interaction analyses demonstrated that the benefit of T-TEER diminished as baseline KCCQ overall summary score increased (P int  < 0.001). Exploratory analyses suggested that much of the health status benefit of T-TEER could be explained by TR reduction and that improvement in health status after T-TEER was strongly correlated with reduced 1-year mortality and heart failure hospitalization., Conclusions: T-TEER with the TriClip system resulted in substantial and sustained health status improvement in patients with severe TR compared with medical therapy alone., Competing Interests: Funding Support and Author Disclosures The TRILUMINATE Pivotal trial was sponsored by Abbott and designed collaboratively by the principal investigators and the sponsor. The present analysis was conducted by Abbott under the direction of the academic authors. Dr Goates is an employee of Abbott. Dr Sorajja has performed unpaid trial activity with Abbott and HighLife; and has received consulting fees from 4C Medical, Abbott Structural, Biosense Webster, Boston Scientific, Edwards Lifesciences, Foldax, Medtronic, Phillips, Shifamed, Siemens, VDyne, and WL Gore. Dr Adams has performed unpaid trial activity with Abbott, NeoChord, and Medtronic; and has received royalty payments for intellectual property with Edwards Lifesciences and Medtronic. Dr von Bardeleben has performed unpaid trial activity with Abbott, DZHK German Center for Cardiovascular Research, Edwards Lifesciences, University of Göttingen IIT trials, Jenscare, Medtronic, Neochord, and Siemens; and has received consulting fees from Abbott, Edwards Lifesciences, Medtronic, Neochord, Philips, and Siemens. Dr Cohen has received research grant support from Abbott, Edwards Lifesciences, Boston Scientific, and Abbott; and has received consulting fees from Abbott, Medtronic, and Edwards Lifesciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: It remains unclear whether clopidogrel is better suited than aspirin as the long-term antiplatelet monotherapy following dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI)., Objectives: This study compared clopidogrel monotherapy following 1 month of DAPT (clopidogrel group) with aspirin monotherapy following 12 months of DAPT (aspirin group) after PCI for 5 years., Methods: STOPDAPT-2 (Short and Optimal Duration of Dual Antiplatelet Therapy 2) is a multicenter, open-label, adjudicator-blinded, randomized clinical trial conducted in Japan. Patients who underwent PCI with cobalt-chromium everolimus-eluting stents were randomized in a 1-to-1 fashion either to clopidogrel or aspirin groups. The primary endpoint was a composite of cardiovascular outcomes (cardiovascular death, myocardial infarction, stroke, or definite stent thrombosis) or major bleeding (TIMI major or minor bleeding)., Results: Among 3,005 study patients (age: 68.6 ± 10.7 years; women: 22.3%; acute coronary syndrome: 38.3%), 2,934 patients (97.6%) completed the 5-year follow-up (adherence to the study drugs at 395 days: 84.7% and 75.9%). The clopidogrel group compared with the aspirin group was noninferior but not superior for the primary endpoint (11.75% and 13.57%, respectively; HR: 0.85; 95% CI: 0.70-1.05; P noninferiority  < 0.001; P superiority  = 0.13), whereas it was superior for the cardiovascular outcomes (8.61% and 11.05%, respectively; HR: 0.77; 95% CI: 0.61-0.97; P = 0.03) and not superior for major bleeding (4.44% and 4.92%, respectively; HR: 0.89; 95% CI: 0.64-1.25; P = 0.51). By the 1-year landmark analysis, clopidogrel was numerically, but not significantly, superior to aspirin for cardiovascular events (6.79% and 8.68%, respectively; HR: 0.77; 95% CI: 0.59-1.01; P = 0.06) without difference in major bleeding (3.99% and 3.32%, respectively; HR: 1.23; 95% CI: 0.84-1.81; P = 0.31)., Conclusions: Clopidogrel might be an attractive alternative to aspirin with a borderline ischemic benefit beyond 1 year after PCI., Competing Interests: Funding Support and Author Disclosures STOPDAPT-2 is funded by Abbott. The funder had no role in the design, data analysis, interpretation, or writing of the report. Dr Watanabe has received personal fees from Abbott; and has received personal fees from Amgen, Pfizer, and Daiichi-Sankyo outside the submitted work. Dr Morimoto has received lecturer’ fees from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi-Sankyo, Japan Lifeline, Kowa, Pfizer, and Tsumura; has received manuscript fees from Bristol Myers Squibb and Pfizer; and has served on the Advisory Board for Novartis and Teijin outside the submitted work. Dr Natsuaki has received honoraria from Abbott Medical Japan, Daiichi-Sankyo, Medtronic, Terumo, Japan Lifeline, Asahi Intecc, Bristol Myers Squibb, Otsuka, Amgen, Sanofi, Takeda, and Bayer. Dr Hibi has received a scholarship donation from Abbott. Dr Kimura has received research grants from Abbott Vascular and Boston Scientific; and serves as an Advisory Board member for Abbott Vascular and Terumo Japan. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Contemporary care patterns/outcomes in high-risk pulmonary embolism (PE) patients are unknown., Objectives: This study sought to characterize the management of high-risk PE patients and identify factors associated with poor outcomes., Methods: A retrospective analysis of the PERT (Pulmonary Embolism Response Team) Consortium Registry was performed. Patients presenting with intermediate-risk PE, high-risk PE, and catastrophic PE (those with hemodynamic collapse) were identified. Patient characteristics were compared with chi-square testing for categorical covariates and Student's t-test for continuous covariates. Multivariable logistic regression was used to assess associations between clinical characteristics and outcomes in the high-risk population., Results: Of 5,790 registry patients, 2,976 presented with intermediate-risk PE and 1,442 with high-risk PE. High-risk PE patients were more frequently treated with advanced therapies than intermediate-risk PE patients (41.9% vs 30.2%; P < 0.001). In-hospital mortality (20.6% vs 3.7%; P < 0.001) and major bleeding (10.5% vs. 3.5%; P < 0.001) were more common in high-risk PE. Multivariable regression analysis demonstrated vasopressor use (OR: 4.56; 95% CI: 3.27-6.38; P < 0.01), extracorporeal membrane oxygenation use (OR: 2.86; 95% CI: 1.12-7.30; P = 0.03), identified clot-in-transit (OR: 2.26; 95% CI: 1.13-4.52; P = 0.02), and malignancy (OR: = 1.70; 95% CI: 1.13-2.56; P = 0.01) as factors associated with in-hospital mortality. Catastrophic PE patients (n = 197 [13.7% of high-risk PE patients]) had higher in-hospital mortality (42.1% vs 17.2%; P < 0.001) than those presenting with noncatastrophic high-risk PE. Extracorporeal membrane oxygenation (13.3% vs. 4.8% P < 0.001) and systemic thrombolysis (25% vs 11.3%; P < 0.001) were used more commonly in catastrophic PE., Conclusions: In the largest analysis of high-risk PE patients to date, mortality rates were high with the worst outcomes among patients with hemodynamic collapse., Competing Interests: Funding Support and Author Disclosures This work was funded through a grant from the PERT Consortium, a 501(c)3 not-for-profit organization. Dr Kobayashi’s institution has received funding for research from Inari medical and Endovascular Engineering. Dr Sethi has received honoraria/consulting fees from Boston Scientific, Janssen, Chiesi, Terumo, and Inari. Dr Parikh has received institutional research funding from Abbott, Boston Scientific, TriReme Medical, Shockwave Medical, Surmodics, Reflow Medical, Concept Medical, Veryan Medical, and MedAlliance; has served as an advisor to Abbott, Boston Scientific, Cordis, Medtronic, and Philips; and has served as a consultant for Terumo, Inari, Penumbra, and Canon. Dr Rosenfield has served as a consultant or on the scientific advisory board for Abbott Vascular, Althea Medical, Angiodynamics, Auxetics, Becton Dickinson, Boston Scientific, Contego, Crossliner, Imperative Care/Truvic, Innova Vascular, Inspire MD, Janssen/Johnson and Johnson, Magneto, Mayo Clinic, MedAlliance, Medtronic, Neptune Medical, Penumbra, Philips, Surmodics, Terumo, Thrombolex, Vasorum, Vantis Vascular, and Vumedi; owns equity or stock options in Access Vascular, Aerami, Althea Medical, Auxetics, Contego, Endospan, Imperative Care/Truvic, Innova Vascular, InspireMD, JanaCare, Magneto, MedAlliance, Neptune Medical, Orchestra, Prosomnus, Shockwave, Skydance, Summa Therapeutics, Thrombolex, Valcare, Vantis Vascular, Vasorum, and Vumedi; his institution has received funding from the National Institutes of Health, Abiomed, Boston Scientific, Novo Nordisk, Penumbra, Gettinge-Atrium; and has served on the Board of Directors of the National PERT Consortium. Dr Lookstein has served on the advisory board for Boston Scientific and Medtronic; has served as a consultant for Penumbra Vascular, Abbott Vascular, Neptune Medical, Imperative Vascular, Becton Dickinson Vascular, Biosense Webster, and Cordis Vascular; and owns equity in Imperative Vascular, Innova Vascular, Thrombolex, and Summa Vascular. Dr Gibson has served as a consultant for Alexion, AstraZeneca, Bayer, Janssen, and CytoSorbents. Dr Khandhar has received consulting fees from Inari Medical. Dr Secemsky has received consulting fees from Abbott, Bayer, BD, Boston Scientific, Cook, Cordis, CSI, HeartFlow, Inari, InfraRedx, Medtronic, Philips, RapidAI, Shockwave, and VentureMed; and his institution has received research funding from the National Institutes of Health/National Heart, Lung, and Blood Institute (K23HL150290), the U.S. Food and Drug Administration, the Society for Cardiovascular Angiography and Interventions, BD, Boston Scientific, Cook, CSI, Laminate Medical, Medtronic, and Philips. Dr Giri has served on the advisory board for and his institution has received research funding from Boston Scientific, Abbott Vascular, Recor Medical, Inari Medical, Edwards, and Abiomed; and owns equity in Endovascular Engineering. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures Funding was provided by the Bill and Melinda Gates Foundation, and the American College of Cardiology Foundation. The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The contents and views expressed in this report are those of the authors and do not necessarily reflect the official views of the National Institutes of Health, the Department of Health and Human Services, the U.S. Government, or the affiliated institutions.

Background: Children with heart disease frequently require anticoagulation for thromboprophylaxis. Current standard of care (SOC), vitamin K antagonists or low-molecular-weight heparin, has significant disadvantages., Objectives: The authors sought to describe safety, pharmacokinetics (PK), pharmacodynamics, and efficacy of apixaban, an oral, direct factor Xa inhibitor, for prevention of thromboembolism in children with congenital or acquired heart disease., Methods: Phase 2, open-label trial in children (ages, 28 days to <18 years) with heart disease requiring thromboprophylaxis. Randomization 2:1 apixaban or SOC for 1 year with intention-to-treat analysis., Primary Endpoint: a composite of adjudicated major or clinically relevant nonmajor bleeding. Secondary endpoints: PK, pharmacodynamics, quality of life, and exploration of efficacy., Results: From 2017 to 2021, 192 participants were randomized, 129 apixaban and 63 SOC. Diagnoses included single ventricle (74%), Kawasaki disease (14%), and other heart disease (12%). One apixaban participant (0.8%) and 3 with SOC (4.8%) had major or clinically relevant nonmajor bleeding (% difference -4.0 [95% CI: -12.8 to 0.8]). Apixaban incidence rate for all bleeding events was nearly twice the rate of SOC (100.0 vs 58.2 per 100 person-years), driven by 12 participants with ≥4 minor bleeding events. No thromboembolic events or deaths occurred in either arm. Apixaban pediatric PK steady-state exposures were consistent with adult levels., Conclusions: In this pediatric multinational, randomized trial, bleeding and thromboembolism were infrequent on apixaban and SOC. Apixaban PK data correlated well with adult trials that demonstrated efficacy. These results support the use of apixaban as an alternative to SOC for thromboprophylaxis in pediatric heart disease. (A Study of the Safety and Pharmacokinetics of Apixaban Versus Vitamin K Antagonist [VKA] or Low Molecular Weight Heparin [LMWH] in Pediatric Subjects With Congenital or Acquired Heart Disease Requiring Anticoagulation; NCT02981472)., Competing Interests: Funding Support and Author Disclosures This trial was supported by the Bristol Myers Squibb/Pfizer Alliance, in collaboration with the NHLBI-funded Pediatric Heart Network (grant numbers: HL135646, HL135665, HL135666, HL135678, HL135680, HL135682, HL135683, HL135685, HL135689, HL135691). Bristol Myers Squibb provided all financing and drugs for this trial; managed the trial data, adjudication process, and clinical sites; and was involved in the design of the study. The Pediatric Heart Network (PHN) provided scientific input on the trial design and contributed organizational infrastructure including the Data and Safety Monitoring Board, Protocol Review Committee, Publications and Presentations Committee, and additional logistical support for United States–based sites. Editorial support was provided by Caudex and was funded by Bristol Myers Squibb. Any publication-related fees will be funded by Bristol Myers Squibb. In collaboration with the trial steering committee, Bristol Myers Squibb was involved in the writing of this manuscript and decision to submit the paper for publication. Dr Payne has received grants or contracts from the National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI), Friedreich Ataxia Research Alliance, and Additional Ventures non-profit organization; has received royalties or license from inventions: Wake Forest University, Larimar Therapeutics, and Indiana University; has received consulting fees from Larimar Therapeutics Inc.; has received support for attending meetings or travel from Indiana University School of Medicine; has 2 patents pending at Indiana University School of Medicine; is chair or is on the Data and Safety Monitoring Board (DSMB) for NIH study on Friedreich Ataxia; has served on the scientific advisory board for Friedreich Ataxia Research Alliance; and has stock in Larimar Therapeutics, Inc. Dr Glatz has received grants or contracts from NIH/NHLBI. Dr Male has received payment or honoraria from Anthos, AstraZeneca, Bayer, Chiesi, Janssen, and Norgine; and has a leadership or fiduciary role in Pediatric Anti-thrombotic Trials Leadership & Steering (Pedi-ATLAS) Group. Dr Brandão has received participation in an advisory committee for AstraZeneca (Andexxa in pediatrics) and Boehringer Ingelheim (dabigatran in children). Dr VanderPluym has received grants or contracts from the Georgia Claire Bowen Foundation; has received consulting fees from AstraZeneca and Merck; and participates in an advisory committee for the Valor Trial (Veriguciat in pediatric heart failure), and Andexxa in pediatrics in Europe. Dr Kochilas has received grants or contracts from NIH/NHLBI, Department of Defense, and Novartis Pharma; and participates in the Mitochondrial transplant study: Boston Children’s Hospital. Dr Stiller has received consulting fees from Janssen and Novartis; and has received payment or honoraria from Bristol Myers Squibb. Dr Cnota has received grants or contracts from NIH/NHLBI and Additional Ventures nonprofit organization; has received support for attending meetings or travel from the American Heart Association CSSP committee; and has participated on the NIH-NHLBI DSMB, Advisory Board for Inozyme Pharma. Dr Rahkonen has received payment or honoraria from Bristol Myers Squibb. Dr Adorisio has received grants or contracts from HORIZON 2022, Ministry of Italian Public Health; and has received consulting fees and payment or honoraria from PTC Therapeutics. Dr Stoica has been a co-applicant on research grants from local charities, National Institute of Health Research, the Health Foundation, and industry (Livanova, Admedus); has received payment or honoraria from LeMaitre Vascular; has received payment for expert testimony; and was audit co-lead in the Society of Cardiothoracic Surgeons of Great Britain and Ireland and at the National Institute of Cardiovascular Outcomes and Research. Dr May has received institutional support for conference fees. Dr Saraiva has a conflict of interest with AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received consulting fees from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment or honoraria from AstraZeneca, Novartis, Merck, Novo Nordisk, Boehringer, Janssen, and Bayer; has received payment for expert testimony from AstraZeneca; has received support for attending meetings or travel from Novo Nordisk, AstraZeneca, and Boehringer; and has participated in the Allbert Einstein Academic Research Organization, Brazil. Dr Rubio has stock in BMS (obtained in 2001). Dr Meador has Concurrent employment with AtriCure effective September 2022. Ms Wheaton has a contract between HealthCore (now known as Carelon Research) and BMS to conduct the SAXOPHONE study. Dr Ajavon-Hartmann and Ms Mills are employees of and have stock options in Bristol Myers Squibb. Drs Jarugula, Reedy, and Dyme and Ms Carlson-Taneja are employees of Bristol Myers Squibb. Dr Monagle has received patents planned, issued, or pending from University of Melbourne and McMaster University: No commercial interests or connections since 2011. No current licensing agreements and no ongoing negotiations to license. Expect patents to expire in the next couple of years - Thrombin generation assay. Inventors: Berry LR, Ignjatovic V, Monagle PT, Chan AKC. U.S. patent, patent no. 8138308, “Modified Peptide Substrate”, issued 20 March 2012 “Enzyme Measurement Assay Using a Modified Substrate Comprising a Substrate Attached to a Macromolecule via a Spacer”: India patent no. 244241, issued November 25, 2010; Europe patent application, serial no. 06840527.3, issued October 2019; China patent application, serial no. 200680053447, filed December 21, 2006; and Japan patent application, serial no. 2008-547812, filed December 21, 2006. Dr Monagle has participated in Bayer Einstein junior suite of studies (Rivaroxaban in children): steering committee and writing committee; is an unpaid site investigator for the Bristol Myers Squibb SAXOPHONE study (apixaban in children): steering committee and writing committee; has been a site investigator (Unpaid, Ongoing) for Janssen; is an unpaid advisory board member for Milvexian; is an unpaid advisory board member for Takeda; is an unpaid advisory board member for Ceprotinin; and is an Associate Investigator for AstraZeneca, Takeda, Stago, Bayer, Janssen, and Pfizer. The views expressed in this manuscript are those of the authors and do not necessarily represent the views of the National Heart, Lung, and Blood Institute, the National Institutes of Health, the U.S. Department of Health and Human Services, or Bristol Myers Squibb/Pfizer Alliance. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. All rights reserved.)

Background: Lp(a) (lipoprotein[a])-lowering therapy to reduce cardiovascular disease is under investigation in phase 3 clinical trials. High Lp(a) may be implicated in peripheral artery disease (PAD), abdominal aortic aneurysms (AAAs), and major adverse limb events (MALE)., Objectives: The authors investigated the association of high Lp(a) levels and corresponding LPA genotypes with risk of PAD, AAA, and MALE., Methods: The authors included 108,146 individuals from the Copenhagen General Population Study. During follow-up, 2,450 developed PAD, and 1,251 AAAs. Risk of MALE was assessed in individuals with PAD at baseline and replicated in the Copenhagen City Heart Study., Results: Higher Lp(a) was associated with a stepwise increase in risk of PAD and AAA (P for trend <0.001). For individuals with Lp(a) levels ≥99th (≥143 mg/dL, ≥307 nmol/L) vs <50th percentile (≤9 mg/dL, ≤17 nmol/L), multivariable-adjusted HRs were 2.99 (95% CI: 2.09-4.30) for PAD and 2.22 (95% CI: 1.21-4.07) for AAA. For individuals with PAD, the corresponding incidence rate ratio for MALE was 3.04 (95% CI: 1.55-5.98). Per 50 mg/dL (105 nmol/L) genetically higher Lp(a) risk ratios were 1.39 (95% CI: 1.24-1.56) for PAD and 1.21 (95% CI: 1.01-1.44) for AAA, consistent with observational risk ratios of 1.33 (95% CI: 1.24-1.43) and 1.27 (95% CI: 1.15-1.41), respectively. In women smokers aged 70 to 79 years with Lp(a) <50th and ≥99th percentile, absolute 10-year risks of PAD were 8% and 21%, and equivalent risks in men 11% and 29%, respectively. For AAA, corresponding risks were 2% and 4% in women, and 5% and 12% in men., Conclusions: High Lp(a) levels increased risk of PAD, AAA, and MALE by 2- to 3-fold in the general population, opening opportunities for prevention given future Lp(a)-lowering therapies., Competing Interests: Funding Support and Author Disclosures The study was founded by the Department of Clinical Biochemistry, Copenhagen University Hospital–Herlev and Gentofte, Gangstedfonden, and was supported by a research grant from the Danish Cardiovascular Academy (grant number 2022007-HF), which is funded by the Novo Nordisk Foundation, grant number NNF20SA0067242 and The Danish Heart Foundation. The sponsors of the study had no role in study design, data collection, data analysis, data interpretation, writing of the paper, or decision to submit the manuscript for publication. Dr Nordestgaard has consultancies with Abbott, Akcea, Amarin, Amgen, AstraZeneca, Denka, Esperion, Kowa, Lilly, Mankind, Novartis, Novo Nordisk, Regeneron, Sanofi, Silence Therapeutics, and Ultragenyx. Dr Kamstrup has lecture honoraria or consultancies from Physicians’ Academy for Cardiovascular Education, PCSK9 Forum, Silence Therapeutics, and Novartis. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Competing Interests: Funding Support and Author Disclosures The authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Background: Lipoprotein(a) (Lp[a]) has been identified as an emerging risk factor for adverse cardiovascular (CV) outcomes, including heart failure. However, the connections among Lp(a), myocardial fibrosis (interstitial and replacement), and cardiac remodeling as pathways to CV diseases remains unclear., Objectives: This study investigated the relationship between Lp(a) levels and myocardial fibrosis by cardiac magnetic resonance (CMR) T1 mapping and late gadolinium enhancement, as well as cardiac remodeling by cine CMR, in the MESA (Multi-Ethnic Study of Atherosclerosis) cohort., Methods: The study included 2,040 participants with baseline Lp(a) measurements and T1 mapping for interstitial myocardial fibrosis (IMF) evaluation in 2010. Lp(a) was analyzed as a continuous variable (per log unit) and using clinical cutoff values of 30 and 50 mg/dL. Multivariate linear and logistic regression were used to assess the associations of Lp(a) with CMR measures of extracellular volume (ECV fraction [ECV%]), native T1 time, and myocardial scar, as well as parameters of cardiac remodeling, in 2,826 participants., Results: Higher Lp(a) levels were associated with increased ECV% (per log-unit Lp[a]; β = 0.2%; P = 0.007) and native T1 time (per log-unit Lp[a]; β = 4%; P < 0.001). Similar relationships were observed between elevated Lp(a) levels and a higher risk of clinically significant IMF defined by prognostic thresholds per log-unit Lp(a) of ECV% (OR: 1.20; 95% CI: 1.04-1.43) and native T1 (OR: 1.2; 95% CI: 1.1-1.4) equal to 30% and 955 ms, respectively. Clinically used Lp(a) cutoffs (30 and 50 mg/dL) were associated with greater prevalence of myocardial scar (OR: 1.85; 95% CI: 1.1-3.2 and OR: 1.9; 95% CI: 1.1-3.4, respectively). Finally, higher Lp(a) levels were associated with left atrial enlargement and dysfunction., Conclusions: Elevated Lp(a) levels are linked to greater subclinical IMF, increased myocardial scar prevalence, and left atrial remodeling., Competing Interests: Funding Support and Author Disclosures This work was supported by contracts HHSN268201500003I, N01-HC-95159, N01-HC95160, N01-HC-95161, N01-HC-95162, N01-HC-95163, N01-HC-95164, N01-HC-95165, N01HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 and by grant R01- HL-127659 from the National Heart, Lung, and Blood Institute; by grants UL1-TR-000040, UL1-TR001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences; and by a grant from Bayer Healthcare for the use of gadolinium contrast agent. The authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)