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Abstract Background Previous reports on lymphocyte subpopulations in systemic sclerosis (SSc) are conflicting. Therefore, we aimed to investigate the lymphocyte subsets in SSc patients who were not on immunosuppressive therapy. Methods Lymphocyte subsets were assessed in the peripheral blood of SSc patients (n = 29) and healthy controls (n = 29) using the four colour flow cytometry method. Correlation studies were also performed in order to assess the relationship between lymphocyte subsets and clinical parameters. Results The absolute count of lymphocytes (P = 0.0042), CD3+ (P = 0.0014), CD4+ (P = 0.0070), CD8+ (P = 0.021), and CD19+ cells (P = 0.024) was significantly decreased in SSc patients when compared to healthy controls. CD4+/CD8+ ratio and the absolute count of CD56+ cells observed in SSc patients did not significantly differ from controls (P = 0.165; P = 0.632, respectively). There was no substantial relationship between the lymphocyte subset levels and clinical features (i.e., SSc subtype, autoantibody profiles, organ involvement), except for a significant inverse correlation of CD19+ cells and the modified Rodnan skin score (r = -0.43, P = 0.020). Conclusion Our data support previous reports indicating that subsets of T lymphocytes as well as B lymphocytes play a role in the pathogenesis of SSc.

We report a case of subacute cutaneous lupus erythematosus (SCLE) following mRNA vaccination with the Pfizer mRNA vaccine BNT162b2, and summarize the current literature on CLE occurring after COVID-19 vaccination. Induction and exacerbation of subacute cutaneous lupus erythematosus following mRNA-based or adenoviral vector-based SARS-CoV-2 vaccination Evidence is accumulating that COVID-19 vaccines might induce or exacerbate autoimmune rheumatic diseases. [Extracted from the article]

Studies of chemical signals in vertebrates typically target single species; however, a broader understanding of olfactory communication may derive from comparative studies. We collected urine from 12 species representing most families of strepsirrhine primates - an excellent model clade because of variation in scent marking and socioecology. Using SPDE/GC-MS, we identified the volatile chemical composition of male and female urine from six 'urine marking' species and six glandular or 'non-urine marking' species. We found no sex differences, but as predicted, urine markers expressed the most chemically complex and distinctive urine. More distantly related species had more dissimilar urinary profiles, suggesting gradual signal evolution. Reconstructing ancestral chemical profiles revealed different evolutionary trajectories for urine and non-urine markers. We suggest that urine marking is an ancestral behaviour related to solitary, nocturnal living and that parallel evolutionary shifts towards greater reliance on derived glandular marking occurred in a family (Lemuridae) characterized by diurnality and sociality. [ABSTRACT FROM AUTHOR]

Aims: Exercise training (ET) is an effective therapy in heart failure with preserved ejection fraction (HFpEF), but the influence of different ET characteristics is unclear. We aimed to evaluate the associations between ET frequency, duration, intensity [% heart rate reserve (%HRR)] and estimated energy expenditure (EEE) with the change in peak oxygen consumption (V̇O2) over 3 months of moderate continuous training (MCT, 5×/week) or high-intensity interval training (HIIT, 3×/week) in HFpEF., Methods and Results: ET duration and heart rate (HR) were recorded with a smartphone application. EEE was calculated using the HR data during ET and the individual HR-V̇O2 relationships during cardiopulmonary exercise testing. Differences between groups and associations between ET characteristics and peak V̇O2 change were assessed with linear regression analyses. Peak V̇O2 improved by 9.2 ± 13.2% after MCT and 8.7 ± 15.9% after HIIT (P = 0.67). The average EEE of 1 HIIT session was equivalent to ∼1.42 MCT sessions and when adjusted for EEE, the mean difference between MCT and HIIT was -0.1% (P = 0.98). For both MCT and HIIT, peak V̇O2 change was positively associated with ET frequency (MCT: R2 = 0.103; HIIT: R2 = 0.149) and duration/week (MCT: R2 = 0.120; HIIT: R2 = 0.125; all P < 0.05). Average %HRR was negatively associated with peak V̇O2 change in MCT (R2 = 0.101; P = 0.034), whereas no significant association was found in HIIT (P = 0.234). Multiple regression analyses explained ∼1/3 of the variance in peak V̇O2 change., Conclusion: In HFpEF, isocaloric HIIT and MCT seem to be equally effective over 3 months. Within each mode, increasing ET frequency or duration/week may be more effective to improve peak V̇O2 than increasing ET intensity., Competing Interests: Conflict of interest: Dr Mueller reported personal fees (advisory board) from Bristol Myers Squibb outside the submitted work. Dr Winzer reported grants from Boehringer Ingelheim, and personal fees from Amarin, Amgen, AstraZeneca, Daiichi Sankyo, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, Novartis and Pfizer outside the submitted work. Dr Gevaert reported receiving lecture/advisory fees paid to his institution by Abbott, AstraZeneca, Boehringer Ingelheim, Novartis, Johnson and Johnson, and Menarini outside the submitted work. Dr Edelmann reported personal fees from AstraZeneca, Bayer, Berlin Chemie, Boehringer Ingelheim, CVRx, Medtronic, Merck, MSD, Novartis, Pfizer, PharmaCosmos, Resmed, Servier and Vifor Pharma, non-financial support from Novartis, and grants from AstraZeneca, Boehringer Ingelheim, Servier and Thermo Fischer outside the submitted work. Dr Kitzman has been a consultant for AstraZeneca, Pfizer, Corvia Medical, Bayer, Boehringer Ingleheim, NovoNorDisk, Rivus, and St. Luke’s Medical Center; received grant support from US National Institutes of Health (grants U01AG076928; R01AG078153; R01AG045551; R01AG18915; P30AG021332; U24AG059624; and U01HL160272), Novartis, AstraZeneca, Bayer, Pfizer, Novo NorDisk, Rivus, and St. Luke’s Medical Center outside the submitted work; and owns stock in Gilead Sciences. Dr Linke reported grant/research support from Edwards Lifesciences and Novartis, consultant fees from Edwards Lifesciences, Boston Scientific, Abiomed, Novartis, Meril, Pfizer, AstraZeneca, Boehringer Ingelheim, Abbott, MSD, Corvia Medical, and Daiichi Sankyo outside the submitted work, and individual stocks/stock options from Transverse Medical, Picardia and Filterlex. Dr Pieske reported institutional grants from AstraZeneca, Bayer Healthcare and Boston Scientific; personal fees for Steering Committee, consulting, and speaker services from Bayer Healthcare, MSD, AstraZeneca, Boehringer Ingelheim, Novartis, Boston Scientific and Abbott outside the submitted work; and holds minor shares in ICTS GmbH (Imaging in Clinical Trials Services). Dr Van Craenenbroeck reported receiving grants from Vifor Pharma outside the submitted work. Dr Halle reported receiving personal fees from Abbott, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, sanofi-aventis, Novartis, Medical Park (consulting fees and honoraria for lectures) and being the past-president of the European Association of Preventive Cardiology (2020–22) outside the submitted work. No other potential conflicts of interest were reported., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: Reverse ventricular remodelling, defined as a decrease in left ventricular end-systolic volume indexed to body surface area (LVESVI) or an increase in left ventricular ejection fraction (LVEF), is associated with improved clinical outcomes in patients with heart failure with reduced ejection fraction (HFrEF). However, the underlying pathophysiological mechanisms remain unclear., Methods and Results: We evaluated paired core-lab assessed echocardiograms and measurements of 92 biomarkers at baseline and 8 months thereafter in 419 participants with HFrEF. Reverse ventricular remodelling was defined as a >5% LVEF increase or >15% LVESVI relative decrease between baseline and 8 months. We evaluated the association between baseline biomarkers and their changes with reverse ventricular remodelling in the prospectively randomized controlled VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) trial. Of 419 patients (median age 66 [interquartile range 57-74] years, 27.4% women), 206 (49.2%) had reverse ventricular remodelling (either a 5% LVEF increase or a 15% LVESVI decrease). There were no differences in baseline biomarker concentrations between patients with versus those without reverse ventricular remodelling on follow-up. However, in patients with reverse ventricular remodelling there were significant decreases in biomarkers relating to inflammation and cardiac metabolism; particularly the tumour necrosis factor superfamily member 13B (ratio 0.82, 95% confidence interval [CI] 0.77-0.88), growth differentiation factor-15 (ratio 0.74, 95% CI 0.66-0.84), and insulin-like growth factor binding protein 7 (ratio 0.80, 95% CI 0.73-0.88)., Conclusions: Reverse ventricular remodelling in patients with HFrEF is associated with a decrease of biomarkers related to inflammation and cardiac metabolism., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Atrial fibrillation (AF) is common in heart failure (HF) and negatively impacts outcomes. The role of ablation-based rhythm control in patients with AF and HF with preserved (HFpEF) or mildly reduced ejection fraction (HFmrEF) is not known. The CABA-HFPEF-DZHK27 (CAtheter-Based Ablation of atrial fibrillation compared to conventional treatment in patients with Heart Failure with Preserved Ejection Fraction) trial will determine whether early catheter ablation for AF can prevent adverse cardiovascular outcomes in patients with HFpEF or HFmrEF., Methods: CABA-HFPEF-DZHK27 (NCT05508256) is an investigator-initiated, prospective, randomized, open, interventional multicentre strategy trial with blinded outcome assessment. Approximately 1548 patients with paroxysmal or persistent AF diagnosed within 24 months prior to enrolment and HFpEF or HFmrEF will be randomized to early catheter ablation within 4 weeks after randomization or to usual care. All patients receive anticoagulation, rate control, and HF management according to current guideline recommendations. Usual care can include rhythm control in symptomatic patients. Patients will be followed until the end of the trial for the primary outcome, a composite of cardiovascular death, stroke, and total unplanned hospitalizations for HF or acute coronary syndrome. The safety outcome comprises complications of catheter ablation and death. The trial is powered for a rate ratio of 0.75 (two-sided alpha = 0.05, 1-beta = 0.8)., Conclusion: CABA-HFPEF-DZHK27 will define the role of systematic and early catheter ablation in patients with AF and HFpEF or HFmrEF., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Importance: Elevated values of high-sensitivity cardiac troponin (hs-cTn) are common in patients with acute ischemic stroke and are associated with poor prognosis. However, diagnostic and therapeutic implications in patients with ischemic stroke remain unclear., Objective: To identify factors indicative of myocardial infarction (MI) in patients with acute ischemic stroke and hs-cTn elevation. The primary hypothesis was that a dynamic change of hs-cTn values (>50% change) in patients with acute ischemic stroke indicates MI., Design, Setting, and Participants: This cross-sectional study was a prospective, observational study with blinded end-point assessment conducted across 26 sites in Germany. Patients were included if they had acute ischemic stroke within 72 hours and either (1) highly elevated hs-cTn values on admission (>52 ng/L) or (2) hs-cTn levels above the upper limit of normal and a greater than 20% change at repeated measurements. Patients were enrolled between August 2018 and October 2020 and had 1 year of follow-up. Statistical analysis was performed between April 2022 and August 2023., Exposure: Standardized electrocardiography, echocardiography, and coronary angiography., Main Outcome and Measures: Diagnosis of MI as adjudicated by an independent end-point committee based on the findings of electrocardiography, echocardiography, and coronary angiography., Results: In total, 254 patients were included. End points were adjudicated in 247 patients (median [IQR] age, 75 [66-82] years; 117 were female [47%] and 130 male [53%]). MI was present in 126 of 247 patients (51%) and classified as type 1 MI in 50 patients (20%). Dynamic change in hs-cTn value was not associated with MI in univariable (32% vs 38%; χ2 P = .30) or adjusted comparison (odds ratio, 1.05; 95% CI, 0.31-3.33). The baseline absolute hs-cTn value was independently associated with type 1 MI. The best cutoffs for predicting type 1 MI were at hs-cTn values 5 to 10 times the upper limit normal., Conclusions and Relevance: This study found that in patients with acute ischemic stroke, a dynamic change in hs-cTn values did not identify MI, underscoring that dynamic changes do not identify the underlying pathophysiological mechanism. In exploratory analyses, very high absolute hs-cTn values were associated with a diagnosis of type 1 MI. Further studies are needed how to best identify patients with stroke who should undergo coronary angiography.

Background: In VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction), vericiguat compared with placebo reduced cardiovascular death or heart failure (HF) hospitalization in patients with HF with reduced ejection fraction., Objectives: This study explored the association between vericiguat and recurrent hospitalizations and subsequent mortality after HF hospitalization., Methods: The treatment effect of vericiguat on the burden of HF hospitalizations was evaluated by assessing total HF hospitalization and cardiovascular death in the overall trial and based on baseline N-terminal pro-B-type natriuretic peptide levels with and without adjustment for VICTORIA model covariates (ie, baseline variables associated with the primary endpoint) assessed via the Andersen-Gill method. Associations between vericiguat and recurrent hospitalization and mortality adjusted for VICTORIA model covariates are reported., Results: There were 1,222 total HF hospitalizations and cardiovascular deaths among 2,526 patients in the vericiguat group and 1,336 total events among 2,524 patients in the placebo group (unadjusted HR: 0.89 [95% CI: 0.81-0.97] and adjusted HR: 0.92 [95% CI: 0.84-1.01]). In the subgroup with N-terminal pro-B-type natriuretic peptide levels ≤2,816 pg/mL (ie, Q1 and Q2; median or below), there was a suggestion of a benefit with vericiguat (adjusted HRs of 0.80 [95% CI: 0.64-1.01] and 0.77 [95% CI: 0.62-0.94], respectively) compared with those above this value (adjusted HRs of 1.12 [95% CI: 0.93-1.34] and 0.87 [95% CI: 0.74-1.04] for Q3 and Q4). There was no significant difference in treatment effect between patients with vs without an HF hospitalization. After HF hospitalization, the all-cause mortality rate (events per 100 patient-years) was 48.6 for vericiguat and 44.1 for placebo., Conclusions: Additional investigation of the association between vericiguat and cardiovascular death and total HF hospitalizations by recurrent event analysis did not show a statistically significant reduction in events. Mortality was high after HF hospitalization, emphasizing the need for further therapies to reduce morbidity and mortality. (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp & Dohme Corp, a subsidiary of Merck & Company, Inc, and Bayer AG. Dr Mentz has received research support and honoraria from Bayer and Merck Sharp & Dohme Corporation, a subsidiary of Merck & Company, Inc. Dr Butler has received consulting fees from Abbott, Adrenomed, Amgen, Array, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen, LivaNova, Luitpold, Medtronic, Merck, Novartis, Novo Nordisk, Roche, and Vifor. Dr Chiang has received honoraria from AstraZeneca, Bayer, Boehringer Ingelheim, Daiichi Sankyo, Eli Lilly, MSD, Novartis, Pfizer, and Sanofi. Dr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Hernandez has received research grants from Merck, AstraZeneca, Novartis, and Verily; and received honoraria from Merck, Bayer, Amgen, AstraZeneca, and Novartis. Dr Hilkert is an employee of Merck & Company, Inc. Dr Lam has received research grants from Bayer, the National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research & Development LLC, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global LLC, and Radcliffe Group Ltd, Corpus; has a patent pending (PCT/SG2016/050217 & 16/216929); and is a co-founder and nonexecutive director of eKo.ai. Dr O’Connor has received research funding from Merck and consulting fees from Bayer, Dey LP, and the Bristol Myers Squibb Foundation. Dr Pieske has received research support from Boston Scientific and honoraria from Bayer, MSD, Novartis, AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, BMS, Edwards Lifesciences, and Boston Scientific. Dr Ponikowski has received research grants, consulting fees, and Speakers Bureau for Bayer, MSD, Servier, Novartis, Vifor Pharma Ltd, BMS, Boehringer Ingelheim, Respicardia, AstraZeneca, Cibiem, RenalGuard Solutions, and Berlin-Chemie. Dr Roessig is an employee of Bayer AG. Dr Voors has received research support and honoraria from AstraZeneca, BMS, Bayer, Boehringer Ingelheim, Cytokinetics, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Anstrom has received research grants from Merck and the National Institutes of Health. Dr Armstrong has received research grants from Merck, Bayer, Sanofi-Aventis Recherche & Développement, Boehringer Ingelheim, and CSL Limited; and has received consulting fees from Merck, Bayer, AstraZeneca, and Novartis. 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: Metabolic syndrome (MetS) is defined by the presence of central obesity plus ≥two metabolic/cardiovascular risk factors (RF), with inflammation being a major disease-driving mechanism. Structured endurance exercise training (ET) may positively affect these traits, as well as cardiorespiratory fitness (V̇O 2 peak)., Aims: We explore individual ET-mediated improvements of MetS-associated RF in relation to improvements in V̇O 2 peak and inflammatory profile., Methods: MetS patients from two randomized controlled trials, ExMET ( n  = 24) and OptimEx ( n  = 34), had performed 4- or 3-months supervised ET programs according to the respective trial protocol. V̇O 2 peak, MetS-defining RFs (both RCTs), broad blood leukocyte profile, cytokines and plasma proteins (ExMET only) were assessed at baseline and follow-up. Intra-individual changes in RFs were analysed for both trials separately using non-parametric approaches. Associations between changes in each RF over the exercise period ( n -fold of baseline values) were correlated using a non-parametrical approach (Spearman). RF clustering was explored by uniform manifold approximation and projection (UMAP) and changes in RF depending on other RF or exercise parameters were explored by recursive partitioning., Results: Four months of ET reduced circulating leukocyte counts (63.5% of baseline, P  = 8.0e-6), especially effector subtypes. ET response of MetS-associated RFs differed depending on patients' individual RF constellation, but was not associated with individual change in V̇O 2 peak. Blood pressure lowering depended on cumulative exercise duration (ExMET: ≥102 min per week; OptimEx-MetS: ≥38 min per session) and baseline triglyceride levels (ExMET: <150 mg/dl; OptimEx-MetS: <174.8 mg/dl). Neuropilin-1 plasma levels were inversely associated with fasting plasma triglycerides ( R : -0.4, P  = 0.004) and changes of both parameters during the ET phase were inversely correlated ( R : -0.7, P  = 0.0001)., Conclusions: ET significantly lowered effector leukocyte blood counts. The improvement of MetS-associated cardiovascular RFs depended on individual basal RF profile and exercise duration but was not associated with exercise-mediated increase in V̇O 2 peak. Neuropilin-1 may be linked to exercise-mediated triglyceride lowering., Competing Interests: SM reported receiving personal fees from Bristol-Myers Squibb (consulting services) outside the submitted work. MH reported receiving personal fees from Abbott, Amgen, Bristol-Myers Squibb, Daiichi-Sankyo, Medi and Medical Park (consulting fees and honoraria for lectures) and being the past-president of the European Association of Preventive Cardiology (2020–2022) outside the submitted work. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024 Lechner, Kia, von Korn, Dinges, Mueller, Tjønna, Wisløff, Van Craenenbroeck, Pieske, Adams, Pressler, Landmesser, Halle and Kränkel.)

Aim: Exercise intolerance is the central symptom in patients with heart failure with preserved ejection fraction. In the present study, we investigated the adrenergic reserve both in vivo and in cardiomyocytes of a murine cardiometabolic HFpEF model., Methods: 12-week-old male C57BL/6J mice were fed regular chow (control) or a high-fat diet and L-NAME (HFpEF) for 15 weeks. At 27 weeks, we performed (stress) echocardiography and exercise testing and measured the adrenergic reserve and its modulation by nitric oxide and reactive oxygen species in left ventricular cardiomyocytes., Results: HFpEF mice (preserved left ventricular ejection fraction, increased E/e', pulmonary congestion [wet lung weight/TL]) exhibited reduced exercise capacity and a reduction of stroke volume and cardiac output with adrenergic stress. In ventricular cardiomyocytes isolated from HFpEF mice, sarcomere shortening had a higher amplitude and faster relaxation compared to control animals. Increased shortening was caused by a shift of myofilament calcium sensitivity. With addition of isoproterenol, there were no differences in sarcomere function between HFpEF and control mice. This resulted in a reduced inotropic and lusitropic reserve in HFpEF cardiomyocytes. Preincubation with inhibitors of nitric oxide synthases or glutathione partially restored the adrenergic reserve in cardiomyocytes in HFpEF., Conclusion: In this murine HFpEF model, the cardiac output reserve on adrenergic stimulation is impaired. In ventricular cardiomyocytes, we found a congruent loss of the adrenergic inotropic and lusitropic reserve. This was caused by increased contractility and faster relaxation at rest, partially mediated by nitro-oxidative signaling., (© 2024 The Authors. Acta Physiologica published by John Wiley & Sons Ltd on behalf of Scandinavian Physiological Society.)

Background: Peripartum cardiomyopathy (PPCM) is a global disease with substantial morbidity and mortality. The aim of this study was to analyze to what extent socioeconomic factors were associated with maternal and neonatal outcomes., Methods: In 2011, >100 national and affiliated member cardiac societies of the European Society of Cardiology (ESC) were contacted to contribute to a global PPCM registry, under the auspices of the ESC EORP Programme. We investigated the characteristics and outcomes of women with PPCM and their babies according to individual and country-level sociodemographic factors (Gini index coefficient [GINI index], health expenditure [HE] and human developmental index [HDI])., Results: 739 women from 49 countries (Europe [33%], Africa [29%], Asia-Pacific [15%], Middle East [22%]) were enrolled. Low HDI was associated with greater left ventricular (LV) dilatation at time of diagnosis. However, baseline LV ejection fraction did not differ according to sociodemographic factors. Countries with low HE prescribed guideline-directed heart failure therapy less frequently. Six-month mortality was higher in countries with low HE; and LV non-recovery in those with low HDI, low HE and lower levels of education. Maternal outcome (death, re-hospitalization, or persistent LV dysfunction) was independently associated with income. Neonatal death was significantly more common in countries with low HE and low HDI, but was not influenced by maternal income or education attainment., Conclusions: Maternal and neonatal outcomes depend on country-specific socioeconomic characteristics. Attempts should therefore be made to allocate adequate resources to health and education, to improve maternal and fetal outcomes in PPCM., Competing Interests: Declaration of Competing Interest None of the authors have any conflict of interest to declare related to this manuscript., (Copyright © 2023. Published by Elsevier B.V.)

Aims: We aim to characterize the clinical and proteomic profiles of patients at risk of developing heart failure (HF), with and without coronary artery disease (CAD) or prior myocardial infarction (MI)., Methods and Results: HOMAGE evaluated the effect of spironolactone on plasma and serum markers of fibrosis over 9 months of follow-up in participants with (or at risk of having) CAD, and raised natriuretic peptides. In this post hoc analysis, patients were classified as (i) neither CAD nor MI; (ii) CAD; or (iii) MI. Proteomic between-group differences were evaluated through logistic regression and narrowed using backward stepwise selection and bootstrapping. Among the 527 participants, 28% had neither CAD or MI, 31% had CAD, and 41% had prior MI. Compared with people with neither CAD nor MI, those with CAD had higher baseline plasma concentrations of matrix metalloproteinase-7 (MMP-7), galectin-4 (GAL4), plasminogen activator inhibitor 1 (PAI-1), and lower plasma peptidoglycan recognition protein 1 (PGLYRP1), whilst those with a history of MI had higher plasma MMP-7, neurotrophin-3 (NT3), pulmonary surfactant-associated protein D (PSPD), and lower plasma tumour necrosis factor-related activation-induced cytokine (TRANCE). Proteomic signatures were similar for patients with CAD or prior MI. Treatment with spironolactone was associated with an increase of MMP7, NT3, and PGLYRP1 at 9 months., Conclusions: In patients at risk of developing HF, those with CAD or MI had a different proteomic profile regarding inflammatory, immunological, and collagen catabolic processes., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Heart failure (HF) presents manifestations in both cardiac and vascular abnormalities. Pulmonary hypertension (PH) is prevalent in up 50% of HF patients. While pulmonary arterial hypertension (PAH) is closely associated with pulmonary artery (PA) stiffness, the association of HF caused, post-capillary PH and PA stiffness is unknown. We aimed to assess and compare PA stiffness and blood flow hemodynamics noninvasively across HF entities and control subjects without HF using CMR. We analyzed data of a prospectively conducted study with 74 adults, including 55 patients with HF across the spectrum (20 HF with preserved ejection fraction [HFpEF], 18 HF with mildly-reduced ejection fraction [HFmrEF] and 17 HF with reduced ejection fraction [HFrEF]) as well as 19 control subjects without HF. PA stiffness was defined as reduced vascular compliance, indicated primarily by the relative area change (RAC), altered flow hemodynamics were detected by increased flow velocities, mainly by pulse wave velocity (PWV). Correlations between the variables were explored using correlation and linear regression analysis. PA stiffness was significantly increased in HF patients compared to controls (RAC 30.92 ± 8.47 vs. 50.08 ± 9.08%, p < 0.001). PA blood flow parameters were significantly altered in HF patients (PWV 3.03 ± 0.53 vs. 2.11 ± 0.48, p < 0.001). These results were consistent in all three HF groups (HFrEF, HFmrEF and HFpEF) compared to the control group. Furthermore, PA stiffness was associated with higher NT-proBNP levels and a reduced functional status. PA stiffness can be assessed non-invasively by CMR. PA stiffness is increased in HFrEF, HFmrEF and HFpEF patients when compared to control subjects.Trial registration The study was registered at the German Clinical Trials Register (DRKS, registration number: DRKS00015615)., (© 2023. The Author(s).)

Background: Peripartum cardiomyopathy (PPCM) remains an important cause of maternal morbidity and mortality globally. The pathophysiology remains incompletely understood, and the diagnosis is often missed or delayed., Objectives: This study explored the serum proteome profile of patients with newly diagnosed PPCM, as compared with matched healthy postpartum mothers, to unravel novel protein biomarkers that would further an understanding of the pathogenesis of PPCM and improve diagnostic precision., Methods: Study investigators performed untargeted serum proteome profiling using data-independent acquisition-based label-free quantitative liquid chromatography-tandem mass spectrometry on 84 patients with PPCM, as compared with 29 postpartum healthy controls (HCs). Significant changes in protein intensities were determined with nonpaired Student's t-tests and were further classified by using the Boruta algorithm. The proteins' diagnostic performance was evaluated by area under the curve (AUC) and validated using the 10-fold cross-validation., Results: Patients with PPCM presented with a mean left ventricular ejection fraction of 33.5% ± 9.3% vs 57.0% ± 8.8% in HCs (P < 0.001). Study investigators identified 15 differentially up-regulated and 14 down-regulated proteins in patients with PPCM compared with HCs. Seven of these proteins were recognized as significant by the Boruta algorithm. The combination of adiponectin, quiescin sulfhydryl oxidase 1, inter-α-trypsin inhibitor heavy chain, and N-terminal pro-B-type natriuretic peptide had the best diagnostic precision (AUC: 0.90; 95% CI: 0.84-0.96) to distinguish patients with PPCM from HCs., Conclusions: Salient biologic themes related to immune response proteins, inflammation, fibrosis, angiogenesis, apoptosis, and coagulation were predominant in patients with PPCM compared with HCs. These newly identified proteins warrant further evaluation to establish their role in the pathogenesis of PPCM and potential use as diagnostic markers., Competing Interests: Funding Support and Author Disclosures Since the start of EORP, the following companies have supported the whole research program: Abbott Vascular International (2011-2021), Amgen Cardiovascular (2009-2018), AstraZeneca (2014-2021), Bayer AG (2009-2018), Boehringer Ingelheim (2009-2019), Boston Scientific (2009-2012), Bristol-Myers Squibb and Pfizer Alliance (2011-2019), Daiichi Sankyo Europe GmbH (2011-2020), Daiichi Sankyo Europe GmbH and Eli Lilly and Company Alliance (2014-2017), Edwards Lifesciences (2016-2019), Gedeon Richter Plc (2014-2016), Menarini Int Op (2009-2012), Merck Sharp & Dohme–Merck and Co (2011-2014), Novartis Pharma AG (2014-2020), ResMed (2014-2016), Sanofi (2009-2011), Servier (2009-2021), and Vifor (2019-2022). Dr Hoevelmann has received speaker honoraria from Boehringer Ingelheim. Dr Tromp has received support from the National University of Singapore Start-up Grant, the Tier 1 Grant from the Ministry of Education, and the CS-IRG New Investigator Grant from the National Medical Research Council; has received consulting or speaker fees from Daiichi Sankyo, Boehringer Ingelheim, Roche Diagnostics, and Us2.ai; and owns patent US-10702247-B2 unrelated to the present work. Dr Sliwa has funded the proteomic analysis using her unconditional research grants; and has received support from Servier: Institut La Conference Hippocrate for funding of a statistical analysis program. 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.)

Aims: Small studies and observations suggested that exercise training may improve peak oxygen consumption (peakVO 2 ) in patients with advanced heart failure and left ventricular assist device (LVAD). We investigated whether in this patient group a supervised exercise training can improve exercise capacity., Methods and Results: In this multicentre, prospective, randomized, controlled trial, patients with stable heart failure and LVAD were randomly assigned (2:1) to 12 weeks of supervised exercise training or usual care, with 12 weeks of follow-up. The primary endpoint was the change in peakVO 2 after 12 weeks (51 patients provided a power of 90% with an expected group difference in peakVO 2 of 3 ml/kg/min). Secondary endpoints included changes in submaximal exercise capacity and quality of life. Among 64 patients enrolled (97% male, mean age 56 years), 54 were included in the analysis. Mean difference in the change of peakVO 2 after 12 weeks was 0.826 ml/min/kg (95% confidence interval [CI] -0.37, 2.03; p = 0.183). There was a positive effect of exercise training on 6-min walk distance with a mean increase in the intervention group by 43.4 m (95% CI 16.9, 69.9; p = 0.0024), and on the Kansas City Cardiomyopathy Questionnaire physical domain score (mean 14.3, 95% CI 3.7, 24.9; p = 0.0124), both after 12 weeks. The overall adherence was high (71%), and there were no differences in adverse events between groups., Conclusion: In patients with advanced heart failure and LVAD, 12 weeks of exercise training did not improve peakVO 2 but demonstrated positive effects on submaximal exercise capacity and physical quality of life., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Pivotal outcome trials targeting heart failure with preserved (HFpEF) and mildly-reduced ejection fraction (HFmrEF) may have excluded patients at highest risk of poor outcomes. We aimed to assess eligibility for HFpEF/HFmrEF outcome trials in an unselected heart failure cohort and its association with all-cause mortality. Among 32.028 patients presenting to a tertiary care center emergency unit for any reason between August 2018 and July 2019, we identified 407 admissions with evident HFpEF and HFmrEF. Eligibility criteria for pivotal trials CHARM-Preserved, I-PRESERVE, TOPCAT, PARAGON-HF, EMPEROR-Preserved and DELIVER were assessed by chart review. The proportions of admissions fulfilling HFpEF/HFmrEF trial eligibility criteria were 88% for CHARM-Preserved, 40% for I-PRESERVE, 35% for TOPCAT, 28% for PARAGON-HF, 51% for EMPEROR-Preserved, and 49% for DELIVER. During a median follow-up of 1.9 years, death-from-any-cause occurred in 121 cases (30%). Twenty-four-month overall survival estimates for non-eligible and eligible admissions were 53% vs. 76% for CHARM-Preserved (HR=2.32, 95% CI: 1.47-3.67, p<0.001), 62% vs. 87% for I-PRESERVE (HR=2.97, 1.85-4.77, p<0.001), 67% vs. 84% for TOPCAT (HR=2.04, 1.29-3.24, p = 0.002), 68% vs. 85% for PARAGONHF (HR=2.28, 1.33-3.90, p = 0.003), 64% vs. 81% for EMPEROR-Preserved (HR=1.90, 1.27-2.84, p = 0.002), and 65% vs. 80% for DELIVER (HR=1.71, 1.14-2.57, p = 0.010). Exclusion criteria independently predicting death were eGFR <20 ml/min/1.73 m 2 , COPD with home oxygen therapy, and severe valvular heart disease. Conclusively, in a contemporary HFpEF/HFmrEF cohort, non-eligibility for outcome trials predicted for strongly increased mortality. HFpEF/HFmrEF patients at highest mortality risk were likely underrepresented in previous outcome trials and their treatment remains an unmet medical need., Competing Interests: Declaration of Competing Interest The authors declare they have no conflict of interest, (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: COVID-19 is associated with a prothrombotic state. Current guidelines recommend prophylactic anticoagulation upon hospitalization., Methods: COVID-PREVENT, an open-label, multicenter, randomized, clinical trial enrolled patients (≥ 18 years) with moderate to severe COVID-19 and age-adjusted D-dimers > 1.5 upper limit of normal (ULN). The participants were randomly assigned (1:1) to receive either therapeutic anticoagulation with rivaroxaban 20 mg once daily or thromboprophylaxis with a heparin (SOC) for at least 7 days followed by prophylactic anticoagulation with rivaroxaban 10 mg once daily for 28 days or no thromboprophylaxis. The primary efficacy outcome was the D-dimer level and the co-primary efficacy outcome the 7-category ordinal COVID-19 scale by WHO at 7 days post randomization. The secondary outcome was time to the composite event of either venous or arterial thromboembolism, new myocardial infarction, non-hemorrhagic stroke, all-cause death or progression to intubation and invasive ventilation up to 35 days post randomization., Results: The primary efficacy outcome D-dimer at 7 days was not different between patients assigned to therapeutic (n = 55) or prophylactic anticoagulation (n = 56) (1.21 mg/L [0.79, 1.86] vs 1.27 mg/L [0.79, 2.04], p = 0.78). In the whole study population D-dimer was significantly lower at 7 days compared to baseline (1.05 mg/L [0.75, 1.48] vs 1.57 mg/L [1.13, 2.19], p < 0.0001). Therapy with rivaroxaban compared to SOC was not associated an improvement on the WHO 7-category ordinal scale at 7 days (p = 0.085). Rivaroxaban improved the clinical outcome measured by the score in patients with a higher baseline D-dimer  > 2.0 ULN (exploratory analysis; 0.632 [0.516, 0.748], p = 0.026). The secondary endpoint occurred in 6 patients (10.9%) in the rivaroxaban group and in 12 (21.4%) in the SOC group (time-to-first occurrence of the components of the secondary outcome: HR 0.5; 95% CI 0.15-1.67; p = 0.264). There was no difference in fatal or non-fatal major or clinically relevant non-major bleeding between the groups., Conclusions: Therapeutic anticoagulation with rivaroxaban compared to prophylactic anticoagulation with a heparin did not improve surrogates of clinical outcome in patients with moderate to severe COVID-19. Whether initial rivaroxaban at therapeutic doses might be superior to thromboprophylaxis in patients with COVID-19 and a high risk as defined by D-dimer  > 2 ULN needs confirmation in further studies., (© 2023. The Author(s).)

Importance: Left ventricular (LV) hypertrophy contributes to the onset and progression of heart failure (HF), particularly for patients with pre-HF (stage B) for whom no treatment has yet proven effective to prevent transition to overt HF (stage C). The β3-adrenergic receptors (β3ARs) may represent a new target, as their activation attenuates LV remodeling., Objective: To determine whether activation of β3ARs by repurposing a β3AR agonist, mirabegron, is safe and effective in preventing progression of LV hypertrophy and diastolic dysfunction among patients with pre- or mild HF., Design, Setting, and Participants: The Beta3-LVH prospective, triple-blind, placebo-controlled phase 2b randomized clinical trial enrolled patients between September 12, 2016, and February 26, 2021, with a follow-up of 12 months. The trial was conducted at 10 academic hospitals in 8 countries across Europe (Germany, Poland, France, Belgium, Italy, Portugal, Greece, and the UK). Patients aged 18 years or older with or without HF symptoms (maximum New York Heart Association class II) were screened for the presence of LV hypertrophy (increased LV mass index [LVMI] of ≥95 g/m2 for women or ≥115 g/m2 for men) or maximum wall thickness of 13 mm or greater using echocardiography. Data analysis was performed in August 2022., Intervention: Participants were randomly assigned (1:1) to mirabegron (50 mg/d) or placebo, stratified by the presence of atrial fibrillation and/or type 2 diabetes, for 12 months., Main Outcomes and Measures: The primary end points were LVMI determined using cardiac magnetic resonance imaging and LV diastolic function (early diastolic tissue Doppler velocity [E/e'] ratio assessed using Doppler echocardiography) at 12 months. Patients with at least 1 valid measurement of either primary end point were included in the primary analysis. Safety was assessed for all patients who received at least 1 dose of study medication., Results: Of the 380 patients screened, 296 were enrolled in the trial. There were 147 patients randomized to mirabegron (116 men [79%]; mean [SD] age, 64.0 [10.2] years) and 149 to placebo (112 men [75%]; mean [SD] age, 62.2 [10.9] years). All patients were included in the primary intention-to-treat analysis. At 12 months, the baseline and covariate-adjusted differences between groups included a 1.3-g/m2 increase in LVMI (95% CI, -0.15 to 2.74; P = .08) and a -0.15 decrease in E/e' (95% CI, -0.69 to 0.4; P = .60). A total of 213 adverse events (AEs) occurred in 82 mirabegron-treated patients (including 31 serious AEs in 19 patients) and 215 AEs occurred in 88 placebo-treated patients (including 30 serious AEs in 22 patients). No deaths occurred during the trial., Conclusions: In this study, mirabegron therapy had a neutral effect on LV mass or diastolic function over 12 months among patients who had structural heart disease with no or mild HF symptoms., Trial Registration: ClinicalTrials.gov Identifier: NCT02599480.

Introduction: The Berlin Long-term Observation of Vascular Events is a prospective cohort study that aims to improve prediction and disease-overarching mechanistic understanding of cardiovascular (CV) disease progression by comprehensively investigating a high-risk patient population with different organ manifestations., Methods and Analysis: A total of 8000 adult patients will be recruited who have either suffered an acute CV event (CVE) requiring hospitalisation or who have not experienced a recent acute CVE but are at high CV risk. An initial study examination is performed during the acute treatment phase of the index CVE or after inclusion into the chronic high risk arm. Deep phenotyping is then performed after ~90 days and includes assessments of the patient's medical history, health status and behaviour, cardiovascular, nutritional, metabolic, and anthropometric parameters, and patient-related outcome measures. Biospecimens are collected for analyses including 'OMICs' technologies (e.g., genomics, metabolomics, proteomics). Subcohorts undergo MRI of the brain, heart, lung and kidney, as well as more comprehensive metabolic, neurological and CV examinations. All participants are followed up for up to 10 years to assess clinical outcomes, primarily major adverse CVEs and patient-reported (value-based) outcomes. State-of-the-art clinical research methods, as well as emerging techniques from systems medicine and artificial intelligence, will be used to identify associations between patient characteristics, longitudinal changes and outcomes., Ethics and Dissemination: The study was approved by the Charité-Universitätsmedizin Berlin ethics committee (EA1/066/17). The results of the study will be disseminated through international peer-reviewed publications and congress presentations., Study Registration: First study phase: Approved WHO primary register: German Clinical Trials Register: https://drks.de/search/de/trial/DRKS00016852; WHO International Clinical Registry Platform: http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00016852. Recruitment started on July 18, 2017.Second study phase: Approved WHO primary register: German Clinical Trials Register DRKS00023323, date of registration: November 4, 2020, URL: http://www.drks.de/ DRKS00023323. Recruitment started on January 1, 2021., Competing Interests: Competing interests: FE reports grants from German Research Foundation (DFG), grants from German Ministry of Education and Research, grants from the German Herta Foundation; during the conduct of the study; personal fees and non-financial support from Novartis, grants and personal fees from Boehringer Ingelheim, personal fees from CVRx, Pfizer, Medtronic, grants and personal fees from Servier, personal fees from MSD, personal fees from Merck & Co., grants from AstraZeneca, personal fees from Bayer, personal fees from Resmed, personal fees from Berlin Chemie, grants from Thermo Fischer, personal fees from Vifor Pharma, personal fees from PharmaCosmos outside the submitted work; ME reports grants from Bayer and fees paid to the Charité from Abbot, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Daiichi Sankyo, Amgen, Sanofi, Novartis, Pfizer, all outside the submitted work. ME received funding from DFG under Germany’s Excellence Strategy – EXC-2049 – 390688087, Collaborative Research Center ReTune TRR 295- 424778381, BMBF, DZNE, DZHK, EU, Corona Foundation, and Fondation Leducq. HG reports grants from the DFG, the Leducq Foundation, the Federal Ministry of Education and Research (BMBF) and the DZHK during the conduct of the study, outside of the submitted work. UL reports research funding from DZHK; Fondation Leducq; research grants from Novartis, Bayer and Amgen. KM declares that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. DNM received funding for research from Bayer Healthcare, Deutsche Forschungsgemeinschaft and from BMBF. CHN received research grants from German Ministry of Research and Education, German Center for neurodegenerative Diseases (DZNE), DZHK, and speaker and/or consultation fees from Boehringer Ingelheim, Bristol-Myers Squibb, Pfizer Pharma, Abbott, Novartis, Daichii-Sankyo and Alexion all outside the submitted work. BP reports personal fees and other from Bayer Healthcare, personal fees and other from MSD, personal fees and other from Novartis, personal fees from Astrazeneca, grants and personal fees from Servier, personal fees from Medscape, outside the submitted work. No other relationships or activities that could appear to have influenced the submitted work have exist beyond those listed. TP received grants from the BMBF, the Federal Ministry of Food and Agriculture (BMEL), the Federal Ministry for Economic Affairs and Energy (BMWi), the DFG, Deutsche Herzstiftung, German Academic Exchange Service (DAAD). KMSO reports having consultancy fees with BioPorto Diagnostics; having received license revenue related to the use of a neutrophil gelatinase-associated lipocalin assay via Columbia University; receiving research funding from FAST BioMedical, for being a principal investigator of the EMPAKT-CHF trial, and Quark Pharmaceuticals, for being the site principal investigator for QRK309 trial; and being an editorial board member for Kidney International and Kidney International Reports; each outside the submitted work. JSM reports grants from Bayer Healthcare, non-financial support from Siemens healthineers, non-financial support from Circle cardiovascular, non-financial support from Medis, outside the submitted work, and Bayer Healthcare, Advisor. Furthermore, funding for research from the EU, DZHK, Deutsche Herzstiftung. JS received funding for research from DFG and from BMBF. MW received funding for research from DFG, BMBF, Deutsche Gesellschaft für Pneumologie, European Respiratory Society, Marie Curie Foundation, Else Kröner Fresenius Foundation, Capnetz Foundation, International Max Planck Research School, Actelion, Bayer Health Care, Biotest, Boehringer Ingelheim, Noxxon, Pantherna, Quark Pharma, Vaxxilon, and for lectures and advisory from Actelion, Aptarion, Astra Zeneca, Bayer Health Care, Berlin Chemie, Biotest, Boehringer Ingelheim, Chiesi, Glaxo Smith Kline, Novartis, Noxxon, Pantherna, Teva und Vaxxilon. All remaining authors MA, L-HB, K-UE, UG, NH, JK-H, DL, DNM, SKP, SR, GR, KS, OS, BS, SS, RV, JEW do not report potential conflicts of interest., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Atrial contractility and functional reserve in atrial remodeling (AR) without (AR/-AF) or with atrial fibrillation (AR/+AF) are not well characterized. In this study, functional measurements were performed in right atrial muscle strips ( n = 71) obtained from patients ( N = 22) undergoing routine cardiac surgery with either no AR [left atrial (LA) diameter < 40 mm and no history of AF (hAF)], AR/-AF (LA diameter ≥ 40 mm, no hAF), or AR/+AF (hAF and LA diameter ≥ 40 mm or LAEF < 45%). AR/-AF and AR/+AF were associated with a prolongation of half-time-to-peak (HTTP, P < 0.001) and time-to-peak (TTP) contraction ( P < 0.01) when compared with no AR. This effect was seen at baseline and during β-adrenergic stimulation with isoproterenol (Iso). Early relaxation assessed by half-relaxation time (HRT) was prolonged in AR/-AF ( P = 0.03) but not in AR/+AF when compared with no AR at baseline, but this delay in relaxation in AR/-AF was attenuated with Iso. Late relaxation (τ) did not differ between AR/-AF and no AR but was consistently shorter in AR/+AF than no AR before ( P = 0.04) and during Iso ( P = 0.01), indicating accelerated late relaxation in AR/+AF. Relative force increase during Iso was higher ( P = 0.01) and more dispersed ( P = 0.047) in patients with AR/+AF. Relative adrenergic response was unaltered in the myocardium of patients with AR/-AF and AR/+AF. In conclusion, AR/-AF and AR/+AF are associated with changes in myocardial inotropic reserve and contractility. The changes are particularly pronounced in patients with AR/+AF, suggesting that the progression from AR/-AF to AR/+AF is associated with progressive alterations in atrial function that may contribute to arrhythmogenesis. NEW & NOTEWORTHY Mechanical alterations in atrial remodeling without (AR/-AF) and with atrial fibrillation (AR/+AF) have not been studied in detail in human atrial tissue preparations. To our knowledge, this is the first study to compare the mechanical phenotype and inotropic reserve in human atrial myocardial preparations from patients with no atrial remodeling, AR/-AF, and AR/+AF. We identify specific patterns of contractile dysfunction and heterogeneity for both, AR/-AF and AR/+AF, indicating the progression of atrial disease.

Background: The coronary atheroma burden drives major adverse cardiovascular events (MACE) in patients with suspected coronary heart disease (CHD). However, a consensus on how to grade disease burden for effective risk stratification is lacking. The purpose of this study was to compare the effectiveness of common CHD grading tools to risk stratify symptomatic patients., Methods: We analyzed the 5-year outcome of 381 prospectively enrolled patients in the CORE320 international, multicenter study using baseline clinical and cardiac computer-tomography (CT) imaging characteristics, including coronary artery calcium score (CACS), percent atheroma volume, "high-risk" plaque, disease severity grading using the CAD-RADS, and two simplified CAD staging systems. We applied Cox proportional hazard models and area under the curve (AUC) analysis to predict MACE or hard MACE, defined as death, myocardial infarction, or stroke. Analyses were stratified by a history of CHD. Additional forward selection analysis was performed to evaluate incremental value of metrics., Results: Clinical characteristics were the strongest predictors of MACE in the overall cohort. In patients without history of CHD, CACS remained the only independent predictor of MACE yielding an AUC of 73 (CI 67-79) vs. 64 (CI 57-70) for clinical characteristics. Noncalcified plaque volume did not add prognostic value. Simple CHD grading schemes yielded similar risk stratification as the CAD-RADS classification. Forward selection analysis confirmed prominent role of CACS and revealed usefulness of functional testing in subgroup with known CHD., Conclusion: In patients referred for invasive angiography, a history of CHD was the strongest predictor of MACE. In patients without history of CHD, a coronary calcium score yielded at least equal risk stratification vs. more complex CHD grading., (Copyright © 2023 Society of Cardiovascular Computed Tomography. Published by Elsevier Inc. All rights reserved.)

Background: We examined whether the primary composite outcome (cardiovascular death or heart failure hospitalization) was related to differences in background use and dosing of guideline-directed medical therapy in patients with heart failure with reduced ejection fraction enrolled in VICTORIA (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction), a randomized trial of vericiguat versus placebo., Methods: We evaluated the adherence to guideline use of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin receptor-neprilysin inhibitors, beta-blockers, and mineralocorticoid receptor antagonists. We assessed basic adherence; indication-corrected adherence accounting for guideline indications and contraindications; and dose-corrected adherence (indication-corrected adherence+≥50% of drug dose target). Associations between study treatment and the primary composite outcome according to the adherence to guidelines were assessed using multivariable adjustment; adjusted hazard ratios with 95% CIs and P interaction are reported., Results: Of 5050 patients, 5040 (99.8%) had medication data at baseline. For angiotensin-converting enzyme inhibitor, angiotensin-receptor blockers, and angiotensin receptor-neprilysin inhibitors, basic adherence to guidelines was 87.4%, indication-corrected was 95.7%, and dose-corrected was 50.9%. For beta-blockers, basic adherence was 93.1%, indication-corrected was 96.2%, and dose-corrected was 45.4%. For mineralocorticoid receptor antagonists, basic adherence was 70.3%, indication-corrected was 87.1%, and dose-corrected was 82.2%. For triple therapy (angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, or angiotensin receptor-neprilysin inhibitors+beta-blocker+mineralocorticoid receptor antagonist), basic adherence was 59.7%, indication-corrected was 83.3%, and dose-corrected was 25.5%. Using basic or dose-corrected adherence, the treatment effect of vericiguat was consistent across adherence to guidelines groups, with or without multivariable adjustment with no treatment heterogeneity., Conclusions: Patients in VICTORIA were well treated with heart failure with reduced ejection fraction medications. The efficacy of vericiguat was consistent across background therapy with very high adherence to guidelines accounting for patient-level indications, contraindications, and tolerance., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT02861534., Competing Interests: Disclosures Dr Ezekowitz: Research grants from Bayer, Merck, Servier, Amgen Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics; consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr McMullan: Employee of Merck. Dr Westerhout: Consulting fees from Bayer Canada. Dr Piña: Advisory Board member of Relypsa and Vifor. Dr Lopez-Sendon: Grants and personal fees from Bayer, Pfizer, Sanofi, and Boehringer Ingelheim; personal fees from Menarini; grants from Merck and Amgen. Dr Anstrom: Research grants from Merck and the National Institutes of Health. Dr Hernandez: Research grants and personal fees from Merck, AstraZeneca, Novartis, and Boehringer Ingelheim; grants from American Regent; personal fees from Bayer, Amgen, and Boston Scientific. Dr Lam: Grants and personal fees from Merck and Bayer; grants from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; personal fees from Actelion, Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, Us2.ai, Janssen Research & Development LLC, Medscape, Merck, Novartis, Novo Nordisk, Radcliffe Group Ltd., Roche Diagnostics, Sanofi, and WebMD Global LLC; has a patent to PCT/SG2016/050217 pending and a patent to 16/216,929 issued; and is cofounder and nonexecutive director of Us2.ai. Dr O’Connor: Research funding from Merck and consulting fees from Bayer, Dey LP, and Bristol Myers Squibb Foundation. Dr Pieske: Personal fees from Merck, Bayer Healthcare, Novartis, Astra Zeneca, BMS, and Servier. Dr Ponikowski: Research grants from Vifor Pharma Ltd and Servier; consulting fees from MSD, Novartis, Vifor Pharma Ltd, Servier, BMS, Boehringer Ingelheim, Respicardia, AstraZencea, Cibiem, RenalGuardSolution, and Berlin Chemie. Dr Roessig: Employee of Bayer AG. Dr Voors: Research grants from Boehringer Ingelheim and Roche Diagnostics; consulting fees from Merck, Bayer, Amgen, AstraZeneca, Boehringer Ingelheim, Cytokinetics, Myokardia, Novartis, Servier, and Roche Diagnostics. Dr Koglin: Employee of Merck. Dr Armstrong: Grants and personal fees from Merck and Bayer; grants from Sanofi-aventis Recherche & Developpement, Boehringer Ingelheim, and CSL Limited; and personal fees from AstraZeneca and Novartis. Dr Butler: Consulting fees from Bayer, Merck, Amgen, AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Janssen, Luitpold, Medtronic, Novartis, Vifor, and Novo Nordisk.

Background: Age and sex influence treatment and outcomes in patients with heart failure (HF)., Objectives: The authors examined the associations of age and sex with clinical characteristics, background therapies, outcomes, and response to vericiguat in this post hoc analysis of 5,050 VICTORIA (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) patients with HF and reduced ejection fraction; 1,568 (31%) were ≥75 years of age, of whom 445 (24%) were women., Methods: Clinical characteristics were compared across age (<65, 65 to <75, and ≥75 years) and sex. The treatment effect of vericiguat was estimated by age and sex on the primary composite outcome (time to first HF hospitalization or cardiovascular death) using Cox proportional hazards regression., Results: Compared with younger patients, those ≥75 years of age had more class III and IV symptoms, higher N-terminal pro-B-type natriuretic peptide levels, and worse kidney function but had the lowest use of triple therapy. No sex differences in triple therapy existed by age, but achieving target doses of triple therapy was less likely in older patients. Men ≥75 years of age were more than twice as likely to receive defibrillators and 65% more likely to undergo cardiac resynchronization than women. The primary composite outcome was nominally lower in women than men across all age groups. Vericiguat dosing did not differ between sexes in each age group, and its beneficial effect on the primary endpoint was not modified by age (continuous age, P interaction  = 0.169; categorical age, P interaction  = 0.189); and sex (3-way interaction; P = 0.847)., Conclusions: Although elderly women received less intense background HF therapy than men, their prognosis was nominally better. The benefit of vericiguat was independent of age and sex. (Vericiguat Global Study in Subjects with Heart Failure with Reduced Ejection Fraction [HFrEF] [MK-1242-001] [VICTORIA]; NCT02861534)., Competing Interests: Funding Support and Author Disclosures The VICTORIA trial was funded by Merck Sharp and Dohme Corp, a subsidiary of Merck and Co Inc (Rahway, New Jersey, USA), and Bayer AG (Wuppertal, Germany). Dr Lam has received research grants from Bayer, the National Medical Research Council of Singapore, Boston Scientific, Roche Diagnostic, Medtronic, Vifor Pharma, and AstraZeneca; has received consulting fees from Merck, Bayer, Boston Scientific, Roche Diagnostic, Vifor Pharma, AstraZeneca, Novartis, Amgen, Janssen Research and Development, Menarini, Boehringer Ingelheim, Abbott Diagnostics, Corvia, Stealth BioTherapeutics, Novo Nordisk, JanaCare, Biofourmis, Darma, Applied Therapeutics, MyoKardia, Cytokinetics, WebMD Global, Radcliffe Group, and Corpus; has patent PCT/SG2016/050217 pending and patent 16/216929 pending; and is a cofounder and nonexecutive director of eKo.ai. Dr Pieske has received research grants from Merck Sharpe and Dohme, Bayer, and Servier; has received consulting fees from Merck Sharpe and Dohme, Bayer, Servier, Bristol Myers Squibb, MedScape, Daiichi Sankyo, and Novartis; and has received nonfinancial support from Merck Sharpe and Dohme, Bayer, and Novartis. Dr Blaustein is an employee of Merck. Dr Nkulikiyinka is an employee of Bayer. Dr Westerhout has received consulting fees from Bayer. Dr Armstrong has received consulting fees from Merck, Bayer, Boehringer Ingelheim, and Novo Nordisk; and has received research grants from Merck, Bayer, Boehringer Ingelheim/Eli Lilly, and CSL Limited. 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.)

Despite worsening heart failure (HF) being extremely common, expensive, and associated with substantial risk of death, there remain no dedicated clinical practice guidelines for the specific management of these patients. The lack of a management guideline is despite a rapidly evolving evidence-base, as a number of recent clinical trials have demonstrated multiple therapies to be safe and efficacious in this high-risk population. Herein, we propose a framework for treating worsening HF with reduced ejection fraction with the sense of urgency it deserves. This includes treating congestion; managing precipitants; and establishing a foundation of rapid-sequence, simultaneous, and/or in-hospital initiation of quadruple medical therapy for HF with reduced ejection fraction, with the top priority being at least low doses of all 4 medications. Moreover, to maximally reduce residual clinical risk, we further propose consideration of upfront simultaneous use of vericiguat (ie, quintuple medical therapy) and administration of intravenous iron for those who are iron deficient., Competing Interests: Funding Support and Author Disclosures Dr Greene has received research support from the Duke University Department of Medicine Chair’s Research Award, American Heart Association (#929502), National Heart, Lung, and Blood Institute, Amgen, AstraZeneca, Bristol Myers Squibb, Cytokinetics, Merck and Co, Inc, Novartis, Pfizer, and Sanofi; has served on advisory boards for Amgen, AstraZeneca, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Cytokinetics, Roche Diagnostics, scPharmaceuticals, and Sanofi; has served as a consultant for Amgen, Bayer, Boehringer Ingelheim and Eli Lilly, Bristol Myers Squibb, Corteria Pharmaceuticals, CSL Vifor, Merck, Lexicon, PharmaIN, Roche Diagnostics, Sanofi, scPharmaceuticals, Tricog Health, and Urovant Pharmaceuticals; and has received speaker fees from Boehringer Ingelheim, Cytokinetics, Lexicon, and Roche Diagnostics. Dr Bauersachs has received honoraria for lectures/consulting from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Cardior, Corvia, CVRx, Novartis, Pfizer, and Vifor; and has received research support for the department from Zoll, CVRx, and Abiomed. Dr Brugts has received research grants from Abbott, Vifor Pharma; and has received speaker fees from or has served on advisory boards for Abbott, Bayer, Boehringer, Novartis and Vifor Pharma. Dr Ezekowitz has received research grants and consulting fees from Bayer, Merck, Servier, Amgen, Sanofi, Novartis, Cytokinetics, American Regent, and Applied Therapeutics. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, ProSciento Inc, Radcliffe Group Ltd, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and non-executive director of Us2.ai. Dr Lund has received grants from AstraZeneca, Vifor Pharma, Boston Scientific, Boehringer Ingelheim, and Novartis; has served as a consultant for Merck, Vifor Pharma, AstraZeneca, Bayer, Pharmacosmos, MedScape, Sanofi, Lexicon Pharmaceuticals Inc, Myokardia, Boehringer Ingelheim, and Servier; has received speaker honoraria from Abbott, MedScape, Radcliffe, AstraZeneca, Novartis, AnaCardio AB; and has stock ownership in AnaCardio AB. Dr Mentz has received research support and honoraria from Abbott, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Medtronic, Merck, Novartis, Roche, Sanofi, and Vifor. Dr Pieske has been on the steering committee, advisory board, or has received speaker honoraria from Bayer Healthcare, MSD, BMS, Novartis, AstraZeneca, Edwards, Boehringer Ingelheim; and has minor shares in Imaging Clinical Trials Services (ICTS Germany). Dr Ponikowski has served as consultant or on the Advisory Board/Steering Committee/Executive Committee for Abbott Vascular, American Regent, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Impulse Dynamics, Merck, Novartis, Radcliffe Group Ltd, Servier, and Vifor Pharma. Dr Voors has received consultancy fees and/or research grants paid to his employer from Anacardio, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Corteria, Cytokinetics, Merck, Novartis, Novo Nordisk, and Roche Diagnostics. Dr Zieroth has received research grant support, served on advisory boards or speaker engagements for Abbott, Akcea Therapeutics, Inc, AstraZeneca, Amgen, Alnylam, Bayer, Bristol Myers Squibb, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novartis, Novo Nordisk, Otsuka, Pfizer, Servier, and Vifor Pharma; and has served on a clinical trial steering committee or as a national lead for studies sponsored by AstraZeneca, Bayer, Boehringer Ingelheim, Merck, and Novartis. Dr Butler has served as a consultant for Abbott, Adrenomed AG, Amgen, American Regent, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, CVRx, G3 Pharmaceutical, Impulse Dynamics, Innolife, Janssen Pharmaceuticals, LivaNova, Medtronic, Merck, Novartis, Novo Nordisk, Pfizer, Roche, and Vifor Pharma. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)