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Background: Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of hospitalization for heart failure and cardiovascular death among patients with chronic heart failure and a left ventricular ejection fraction of 40% or less. Whether SGLT2 inhibitors are effective in patients with a higher left ventricular ejection fraction remains less certain., Methods: We randomly assigned 6263 patients with heart failure and a left ventricular ejection fraction of more than 40% to receive dapagliflozin (at a dose of 10 mg once daily) or matching placebo, in addition to usual therapy. The primary outcome was a composite of worsening heart failure (which was defined as either an unplanned hospitalization for heart failure or an urgent visit for heart failure) or cardiovascular death, as assessed in a time-to-event analysis., Results: Over a median of 2.3 years, the primary outcome occurred in 512 of 3131 patients (16.4%) in the dapagliflozin group and in 610 of 3132 patients (19.5%) in the placebo group (hazard ratio, 0.82; 95% confidence interval [CI], 0.73 to 0.92; P<0.001). Worsening heart failure occurred in 368 patients (11.8%) in the dapagliflozin group and in 455 patients (14.5%) in the placebo group (hazard ratio, 0.79; 95% CI, 0.69 to 0.91); cardiovascular death occurred in 231 patients (7.4%) and 261 patients (8.3%), respectively (hazard ratio, 0.88; 95% CI, 0.74 to 1.05). Total events and symptom burden were lower in the dapagliflozin group than in the placebo group. Results were similar among patients with a left ventricular ejection fraction of 60% or more and those with a left ventricular ejection fraction of less than 60%, and results were similar in prespecified subgroups, including patients with or without diabetes. The incidence of adverse events was similar in the two groups., Conclusions: Dapagliflozin reduced the combined risk of worsening heart failure or cardiovascular death among patients with heart failure and a mildly reduced or preserved ejection fraction. (Funded by AstraZeneca; DELIVER ClinicalTrials.gov number, NCT03619213.)., (Copyright © 2022 Massachusetts Medical Society.)

Background Understanding the magnitude of cardiovascular disease (CVD) inequalities is the first step toward addressing them. The linkage of socioeconomic and clinical data in universal health care settings provides critical information to characterize CVD inequalities. Methods and Results We employed a prospective cohort design using electronic health records data from all residents of Catalonia aged 18+ between January and December of 2019 (N=6 332 228). We calculated age-adjusted sex-specific prevalence of 5 CVD risk factors (diabetes, hypertension, hyperlipidemia, obesity, and smoking), and 4 CVDs (coronary heart disease, cerebrovascular disease, atrial fibrillation, and heart failure). We categorized income into high, moderate, low, and very low according to individual income (tied to prescription copayments) and receipt of welfare support. We found large inequalities in CVD and CVD risk factors among men and women. CVD risk factors with the largest inequalities were diabetes, smoking, and obesity, with prevalence rates 2- or 3-fold higher for those with very low (versus high) income. CVDs with the largest inequalities were cerebrovascular disease and heart failure, with prevalence rates 2 to 4 times higher for men and women with very low (versus high) income. Inequalities varied by age, peaking at midlife (30-50 years) for most diseases, while decreasing gradually with age for smoking. Conclusions We found wide and heterogeneous inequalities by income in 5 CVD risk factors and 4 CVD. Our findings in a region with a high-quality public health care system and universal coverage stress that strong equity-promoting policies are necessary to reduce disparities in CVD.

Background: To evaluate the association between sex and ventricular arrhythmias (VA) or sudden death (SD) in nonischemic dilated cardiomyopathy, including analysis of potential confounders., Methods and Results: Retrospective cohort study of consecutive patients with DCM referred for cardiac magnetic resonance at 2 tertiary hospitals. The primary combined end point encompassed sustained VA, appropriate implantable cardioverter defibrillator therapies, resuscitated cardiac arrest, and SD. We included 1165 patients with median follow-up of 36 months (interquartile range 20-58 months). The majority of patients (66%) were males. Males and females had similar left ventricular ejection fraction, but the prevalence of late gadolinium enhancement (LGE) at cardiac magnetic resonance was significantly higher among males (48% vs 30%, P < .001). Males had higher cumulative incidence of the primary end point (8% vs 4%, P = .02), and male sex was a significant predictor of the primary end point at univariate analysis (hazard ratio 1.93, P = .02). However, LGE had a major confounding effect in the association between sex and the primary outcome: the hazard ratio of male sex adjusted for LGE was 1.29 (P = .37). LGE+ females had significantly higher cumulative incidence of the primary end point than LGE- males (13% vs 1.8%, P < .001)., Conclusions: In patients with DCM, the prevalence of LGE is significantly higher among males, implying a major confounding effect in the association between male sex and VA or SD. LGE+ females have significantly higher risk than LGE- males. These data do not support the inclusion of sex into risk stratification algorithms for VA or SD in DCM., Competing Interests: Conflict of interest None declared., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Patients hospitalized for acute heart failure experience poor health status, including a high burden of symptoms and physical limitations, and poor quality of life. SGLT2 (sodium-glucose cotransporter 2) inhibitors improve health status in chronic heart failure, but their effect on these outcomes in acute heart failure is not well characterized. We investigated the effects of the SGLT2 inhibitor empagliflozin on symptoms, physical limitations, and quality of life, using the Kansas City Cardiomyopathy Questionnaire (KCCQ) in the EMPULSE trial (Empagliflozin in Patients Hospitalized With Acute Heart Failure Who Have Been Stabilized)., Methods: Patients hospitalized for acute heart failure were randomized to empagliflozin 10 mg daily or placebo for 90 days. The KCCQ was assessed at randomization and 15, 30, and 90 days. The effects of empagliflozin on the primary end point of clinical benefit (hierarchical composite of all-cause death, heart failure events, and a 5-point or greater difference in KCCQ Total Symptom Score [TSS] change from baseline to 90 days) were examined post hoc across the tertiles of baseline KCCQ-TSS. In prespecified analyses, changes (randomization to day 90) in KCCQ domains, including TSS, physical limitations, quality of life, clinical summary, and overall summary scores were evaluated using a repeated measures model., Results: In total, 530 patients were randomized (265 each arm). Baseline KCCQ-TSS was low overall (mean [SD], 40.8 [24.0] points). Empagliflozin-treated patients experienced greater clinical benefit across the range of KCCQ-TSS, with no treatment effect heterogeneity (win ratio [95% CIs] from lowest to highest tertile: 1.49 [1.01-2.20], 1.37 [0.94-1.99], and 1.48 [1.00-2.20], respectively; P for interaction=0.94). Beneficial effects of empagliflozin on health status were observed as early as 15 days and persisted through 90 days, at which point empagliflozin-treated patients experienced a greater improvement in KCCQ TSS, physical limitations, quality of life, clinical summary, and overall summary (placebo-adjusted mean differences [95% CI]: 4.45 [95% CI, 0.32-8.59], P =0.03; 4.80 [95% CI, 0.00-9.61], P =0.05; 4.66 [95% CI, 0.32-9.01], P =0.04; 4.85 [95% CI, 0.77-8.92], P =0.02; and 4.40 points [95% CI, 0.33-8.48], P =0.03, respectively)., Conclusions: Initiation of empagliflozin in patients hospitalized for acute heart failure produced clinical benefit regardless of the degree of symptomatic impairment at baseline, and improved symptoms, physical limitations, and quality of life, with benefits seen as early as 15 days and maintained through 90 days., Registration: URL: https://www., Clinicaltrials: gov; Unique identifier: NCT0415775.

Iron deficiency (ID) is a comorbid condition frequently seen in patients with heart failure (HF). Iron has an important role in the transport of oxygen, and is also essential for skeletal and cardiac muscle, which depend on iron for oxygen storage and cellular energy production. Thus, ID per se , even without anaemia, can be harmful. In patients with HF, ID is associated with a poorer quality of life (QoL) and exercise capacity, and a higher risk of hospitalisations and mortality, even in the absence of anaemia. Despite its negative clinical consequences, ID remains under-recognised. However, it is easily diagnosed and managed, and the recently revised 2021 European Society of Cardiology (ESC) guidelines on HF provide specific recommendations for its diagnosis and treatment. Prospective randomised controlled trials in patients with symptomatic HF with reduced ejection fraction (HFrEF) show that correction of ID using intravenous iron (principally ferric carboxymaltose [FCM]) provides improvements in symptoms of HF, exercise capacity and QoL, and a recent trial demonstrated that FCM therapy following hospitalisation due to acute decompensated HF reduced the risk of subsequent HF hospitalisations. This review provides a summary of the epidemiology and pathophysiology of ID in HFrEF, and practical guidance on screening, diagnosing, and treating ID.

Aims: To evaluate predictors of electrical storm (ES), including chronic total occlusion in an infarct-related coronary artery (infarct-related artery CTO, IRACTO), in a cohort of patients with prior myocardial infarction (MI) and implantable cardioverter-defibrillators (ICD)., Methods: Multicenter observational cohort study including 643 consecutive patients with prior MI and a first ICD implanted between 2005 and 2018 at three tertiary hospitals. All the patients included in the study had undergone a diagnostic coronary angiography before ICD implantation. The variable prior ventricular arrhythmias (VA+) was positive in patients with secondary prevention ICDs and in those with at least one appropriate ICD therapy after primary prevention implantation., Results: During a median follow-up of 42 months 59 patients (9%) suffered ES. The presence of at least one IRACTO not revascularized (IRACTO-NR) was associated with a significantly higher cumulative incidence of ES (14.5% vs 4.8%, p < 0.001). IRACTO-NR maintained a significant association with ES after adjustment for potential confounders (HR 2.3, p = 0.005) and was an independent predictor of ES together with VA+ and LVEF. The best cut-off of LVEF to predict ES was ≤38%. A risk-prediction model based on IRACTO-NR, VA+ and LVEF≤38% identified three categories of ES risk (low, intermediate and high), with progressively increasing cumulative incidence of ES (2.2%, 9% and 20%)., Conclusion: In a cohort of patients with prior MI and ICD, IRACTO-NR is an independent predictor of ES. A new risk-prediction model allowed the identification of three categories of risk, with potentially important clinical implications., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Aims: To evaluate the burden of cardiovascular risk factors and disease (CVD) among five Asian groups living in Catalonia (Spain): Indian, Pakistani, Bangladeshi, Filipino, and Chinese., Methods and Results: Retrospective cohort study using the Catalan Health Surveillance System database including 42 488 Pakistanis, 40 745 Chinese, 21 705 Indians, 9544 Filipinos, and 6907 Bangladeshis; and 5.3 million native individuals ('locals'). We estimated the age-adjusted prevalence (as of 31 December 2019) and incidence (during 2019) of diabetes, hypertension, hyperlipidaemia, obesity, tobacco use, coronary heart disease (CHD), cerebrovascular disease, atrial fibrillation, and heart failure (HF). Bangladeshis had the highest prevalence of diabetes (17.4% men, 22.6% women) followed by Pakistanis. Bangladeshis also had the highest prevalence of hyperlipidaemia (23.6% men, 18.3% women), hypertension among women (24%), and incident tobacco use among men. Pakistani women had the highest prevalence of obesity (28%). For CHD, Bangladeshi men had the highest prevalence (7.3%), followed by Pakistanis (6.3%); and Pakistanis had the highest prevalence among women (3.2%). For HF, the prevalence in Pakistani and Bangladeshi women was more than twice that of locals. Indians had the lowest prevalence of diabetes across South Asians, and of CHD across South Asian men, while the prevalence of CHD among Indian women was twice that of local women (2.6% vs. 1.3%). Filipinos had the highest prevalence of hypertension among men (21.8%). Chinese men and women had the lowest prevalence of risk factors and CVD., Conclusions: In Catalonia, preventive interventions adapted to the risk profile of different Asian immigrant groups are needed, particularly for Bangladeshis and Pakistanis., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Aim: Intravenous ferric carboxymaltose (FCM) has been shown to improve overall quality of life in iron-deficient heart failure with reduced ejection fraction (HFrEF) patients at a trial population level. This FAIR-HF and CONFIRM-HF pooled analysis explored the likelihood of individual improvement or deterioration in Kansas City Cardiomyopathy Questionnaire (KCCQ) domains with FCM versus placebo and evaluated the stability of this response over time., Methods and Results: Changes versus baseline in KCCQ overall summary score (OSS), clinical summary score (CSS) and total symptom score (TSS) were assessed at weeks 12 and 24 in FCM and placebo groups. Mean between-group differences were estimated and individual responder analyses and analyses of response stability were performed. Overall, 760 (FCM, n = 454) patients were studied. At week 12, the mean improvement in KCCQ OSS was 10.6 points with FCM versus 4.8 points with placebo (least-square mean difference [95% confidence interval, CI] 4.36 [2.14; 6.59] points). A higher proportion of patients on FCM versus placebo experienced a KCCQ OSS improvement of ≥5 (58.3% vs. 43.5%; odds ratio [95% CI] 1.81 [1.30; 2.51]), ≥10 (42.4% vs. 29.3%; 1.73 [1.23; 2.43]) or ≥15 (32.1% vs. 22.6%; 1.46 [1.02; 2.11]) points. Differences were similar at week 24 and for CSS and TSS domains. Of FCM patients with a ≥5-, ≥10- or ≥15-point improvement in KCCQ OSS at week 12, >75% sustained this improvement at week 24., Conclusion: Treatment of iron-deficient HFrEF patients with intravenous FCM conveyed clinically relevant improvements in health status at an individual-patient level; benefits were sustained over time in most patients., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: Improving functional capacity is a key goal in heart failure (HF). This pooled analysis of FAIR-HF and CONFIRM-HF assessed the likelihood of improvement or deterioration in 6-min walk test (6MWT) among iron-deficient patients with chronic HF with reduced ejection fraction (HFrEF) receiving ferric carboxymaltose (FCM)., Methods and Results: Data for 760 patients (FCM: n = 454; placebo: n = 306) were analysed. The proportions of patients receiving FCM or placebo who had ≥20, ≥30, and ≥40 m improvements or ≥10 m deterioration in 6MWT at 12 and 24 weeks were assessed. Patients receiving FCM experienced a mean (standard deviation) 31.1 (62.3) m improvement in 6MWT versus 0.1 (77.1) m improvement for placebo at week 12 (difference in mean changes 26.8 [16.6-37.0]). At week 12, the odds [95% confidence interval] of 6MWT improvements of ≥20 m (odds ratio 2.16 [1.57-2.96]; p < 0.0001), ≥30 m (2.00 [1.44-2.78]; p < 0.0001), and ≥40 m (2.29 [1.60-3.27]; p < 0.0001) were greater with FCM versus placebo, while the odds of a deterioration ≥10 m were reduced with FCM versus placebo (0.55 [0.38-0.80]; p = 0.0019). Among patients who experienced 6MWT improvements of ≥20, ≥30, or ≥40 m with FCM at week 12, more than 80% sustained this improvement at week 24., Conclusion: Ferric carboxymaltose resulted in a significantly higher likelihood of improvement and a reduced likelihood of deterioration in 6MWT versus placebo among iron-deficient patients with HF. Of the patients experiencing clinically significant improvements at week 12, the majority sustained this improvement at week 24. These results are supportive of FCM to improve exercise capacity in HF., (© 2022 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: Worse self-care is associated with a higher risk of readmission and mortality in patients with heart failure (HF). Little is known about how the interplay between clinical and psycho-social factors may modulate self-care behaviours in these patients. The aim of our study was to identify clinical, and particularly psycho-social factors associated with worse self-care and assess their interaction inpatients with heart failure., Methods and Results: We conducted an observational, prospective, cohort study of 1,123 consecutive patients with chronic heart failure. Self-care was assessed with the modified European Heart Failure Self-care Behavior Scale 9-item version (EHFSCBS-9), and both clinical and psycho-social profile of the patients included were also meticulously evaluated. A total of 484 patients (43%) were women, mean age was 72 years, and mean left ventricular ejection fraction was 44.5%. In multivariable analyses combining clinical and psycho-social factors, low social support (OR 3.53, 95% CI [2.13-5.86]; p-value <0.001), absence of caregiver support (OR 2.16, 95% CI [1.34 -3.48]; p-value 0.001) and depressive symptoms (OR 2.40, 95% CI [1.53-3.77]; p-value <0.001) were independent determinants of impaired global self-care. Advanced functional class was associated with better self-care (OR 0.43, 95%CI [0.26-0.70]; p-value 0.001). No other clinical factors remained significantly associated with self-care in these joint models. In discrimination analyses, models containing psycho-social determinants outperformed models only containing heart failure -related (clinical) variables (all p-values<0.001)., Conclusion: Impairment in self-care behaviour is strongly determined by psycho-social factors. Specifically, low social support, the lack of caregiver support and the presence of depressive symptoms are the main drivers of the risk of impairment of self-care in heart failure patients. Evaluation of self-care and self-care interventions should be complemented by a comprehensive psycho-social assessment in patients with heart failure., Abbreviations: DAMOCLES, Definition of the neuro-hormonal Activation, Myocardial function, genOmic expressionand CLinical outcomes in hEart failure patients; NYHA, New York Heart Failure Association; GAM, Generalized Additive Model; BMI, Body Mass Index; GDS, GeriatricDepression Scale., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflicts of interest relevant to the content of this manuscript., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Aim: Patients with diabetes mellitus are at high risk of adverse events after percutaneous revascularization, with no differences in outcomes between most contemporary drug-eluting stents. The Cre8 EVO stent releases a formulation of sirolimus with an amphiphilic carrier from laser-dug wells, and has shown clinical benefits in diabetes. We aimed to compare Cre8 EVO stents to Resolute Onyx stents (a contemporary polymer-based zotarolimus-eluting stent) in patients with diabetes., Methods and Results: We did an investigator-initiated, randomized, controlled, assessor-blinded trial at 23 sites in Spain. Eligible patients had diabetes and required percutaneous coronary intervention. A total of 1175 patients were randomly assigned (1:1) to receive Cre8 EVO or Resolute Onyx stents. The primary endpoint was target-lesion failure, defined as a composite of cardiac death, target-vessel myocardial infarction, and clinically indicated target-lesion revascularization at 1-year follow-up. The trial had a non-inferiority design with a 4% margin for the primary endpoint. A superiority analysis was planned if non-inferiority was confirmed. There were 106 primary events, 42 (7.2%) in the Cre8 EVO group and 64 (10.9%) in the Resolute Onyx group [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.44-0.96; Pnon-inferiority < 0.001; Psuperiority = 0.030]. Among the secondary endpoints, Cre8 EVO stents had significantly lower rate than Resolute Onyx stents of target-vessel failure (7.5% vs. 11.1%, HR: 0.67, 95% CI: 0.46-0.99; P = 0.042). Probable or definite stent thrombosis and all-cause death were not significantly different between groups., Conclusion: In patients with diabetes, Cre8 EVO stents were non-inferior to Resolute Onyx stents with regard to target-lesion failure composite outcome. An exploratory analysis for superiority at 1 year suggests that the Cre8 EVO stents might be superior to Resolute Onyx stents with regard to the same outcome., Clinical Trial Registration: ClinicalTrials.gov: NCT03321032., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Aims: The assumption that improved self-care in the setting of heart failure (HF) care necessarily translates into improvements in long-term mortality and/or hospitalization is not well established. We aimed to study the association between self-care and long-term mortality and other major adverse HF events (MAHFE)., Methods and Results: We conducted an observational, prospective, cohort study of 1123 consecutive patients with chronic HF. The primary endpoint was all-cause mortality. We used the European Heart Failure Self-care Behaviour Scale 9-item version (EHFSCBS-9) to measure global self-care (overall score) and three specific dimensions of self-care including autonomy-based adherence, consulting behaviour and provider-based adherence. After a mean follow-up of 3.3 years, all-cause death occurred in 487 patients (43%). In adjusted analysis, higher EHFScBS-9 scores (better self-care) at baseline were associated with lower risk of all-cause death [hazard ratio (HR) 0.993, 95% confidence interval (CI) (0.988-0.997), P-value = 0.002], cardiovascular (CV) death [HR 0.989, 95% CI (0.981-0.996), P-value = 0.003], HF hospitalization [HR 0.993, 95% CI (0.988-0.998), P-value = 0.005], and the combination of MAHFE [HR 0.995, 95% CI (0.991-0.999), P-value = 0.018]. Similarly, impaired global self-care [HR 1.589, 95% CI (1.201-2.127), P-value = 0.001], impaired autonomy-based adherence [HR 1.464, 95% CI (1.114-1.923), P-value = 0.006], and impaired consulting behaviour dimensions [HR 1.510, 95% CI (1.140-1.923), P-value = 0.006] were all associated with higher risk of all-cause mortality., Conclusion: In this study, we have shown that worse self-care is an independent predictor of long-term mortality (both, all-cause and CV), HF hospitalization, and the combinations of these endpoints in patients with chronic HF. Important dimensions of self-care such as autonomy-based adherence and consulting behaviour also determine the risk of all these outcomes in the long term., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Objectives: This report describes the baseline clinical profiles and management of DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial participants and how these compare with those in other contemporary heart failure with preserved ejection fraction trials., Background: The DELIVER trial was designed to evaluate the effects of the sodium-glucose cotransporter-2 inhibitor dapagliflozin on cardiovascular death, heart failure (HF) hospitalization, or urgent HF visits in patients with HF with mildly reduced and preserved left ventricular ejection fraction (LVEF)., Methods: Adults with symptomatic HF and LVEF >40%, with or without type 2 diabetes mellitus, elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels, and evidence of structural heart disease were randomized to dapagliflozin 10 mg once daily or matching placebo., Results: A total of 6,263 patients were randomized (mean age: 72 ± 10 years; 44% women; 45% type 2 diabetes mellitus; 45% with body mass index ≥30 kg/m 2 ; and 57% with history of atrial fibrillation or flutter). Most participants had New York Heart Association functional class II symptoms (75%). Baseline mean LVEF was 54.2 ± 8.8% and median NT-proBNP of 1,399 pg/mL (IQR: 962 to 2,210 pg/mL) for patients in atrial fibrillation/flutter compared with 716 pg/mL (IQR: 469 to 1,281 pg/mL) in those who were not. Patients in both hospitalized and ambulatory settings were enrolled, including 10% enrolled in-hospital or within 30 days of a hospitalization for HF. Eighteen percent of participants had HF with improved LVEF., Conclusions: DELIVER is the largest and broadest clinical trial of this population to date and enrolled high-risk, well-treated patients with HF with mildly reduced and preserved LVEF. (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure [NCT03619213])., Competing Interests: Funding Support and Author Disclosures The DELIVER study was funded by AstraZeneca. Dr Solomon has received research grants from Actelion, Alnylam, Amgen, AstraZeneca, Bellerophon, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos, Gilead, GlaxoSmithKline, Ionis, Lilly, Mesoblast, MyoKardia, National Institutes of Health/NHLBI, Neurotronik, Novartis, NovoNordisk, Respicardia, Sanofi Pasteur, Theracos, US2.AI; and has consulted for Abbott, Action, Akros, Alnylam, Amgen, Arena, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardior, Cardurion, Corvia, Cytokinetics, Daiichi-Sankyo, GlaxoSmithKline, Lilly, Merck, Myokardia, Novartis, Roche, Theracos, Quantum Genomics, Cardurion, Janssen, Cardiac Dimensions, Tenaya, Sanofi-Pasteur, Dinaqor, Tremeau, CellProThera, Moderna, American Regent, and Sarepta. Dr Vaduganathan has received research grant support or served on advisory boards for American Regent, Amgen, AstraZeneca, Bayer AG, Baxter Healthcare, Boehringer Ingelheim, Cytokinetics, Lexicon Pharmaceuticals, Novartis, Pharmacosmos, Relypsa, Roche Diagnostics, and Sanofi, speaker engagements with Novartis and Roche Diagnostics, and participates on clinical endpoint committees for studies sponsored by Galmed and Novartis. Dr Claggett has received consulting fees from Boehringer Ingelheim. Dr De Boer’s institution, the UMCG, has received research grants and fees (outside the submitted work) from AstraZeneca, Abbott, Boehringer Ingelheim, Cardio Pharmaceuticals Gmbh, Ionis Pharmaceuticals, Inc, Novo Nordisk, and Roche. Dr de Boer has received speaker fees from Abbott, AstraZeneca, Bayer, Novartis, and Roche (outside the submitted work). Dr DeMets has received consulting fees from Frontier Science, Actelion, Bristol Myers Squibb, Medtronic, Boston Scientific, GlaxoSmithKline, and Merck; and has received consulting fees and is the owner of DL DeMets Consulting. Dr Hernandez has received research support from American Regent, AstraZeneca, Boehringer Ingelheim, Merck, Novartis, and Verily; and has served as a consultant or on the Advisory Board for Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Bristol Myers Squibb, Cytokinetics, Myokardia, Merck, Novartis, and Vifor. Dr Inzucchi has served on clinical trial committees or as a consultant to AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lexicon, Merck, Pfizer, vTv Therapeutics, Abbott, and Esperion; and has given lectures sponsored by AstraZeneca and Boehringer Ingelheim. Dr Kosiborod has received research grant support from AstraZeneca, and Boehringer Ingelheim; has served as a consultant or on an advisory board for Amgen, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Esperion Therapeutics, Janssen, Merck (Diabetes and Cardiovascular), Novo Nordisk, Sanofi, and Vifor Pharma; has received other research support from AstraZeneca; and has received honorarium from AstraZeneca, Boehringer Ingelheim, and Novo Nordisk. Dr Lam is supported by a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from AstraZeneca, Bayer, Boston Scientific, and Roche Diagnostics; has served as a consultant or on the advisory board/steering committee/executive committee for 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; and serves as the cofounder and non-executive director of Us2.ai. Dr Martinez has received personal fees from AstraZeneca. Drs Shah and Belohjavek have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Chiang has received honoraria and consultation fees from AstraZeneca, Boehringer Ingelheim, Daiichi-Sankyo, Eli Lilly, Merck Sharp & Dohme, Novartis, Pfizer, and Sanofi. Dr Borleffs has received speaker fees and institutional research support from AstraZeneca; has received speaker fees from Novartis; and has received institutional research support from Boehringer Ingelheim. Dr Comin-Comet has received personal and institutional financial support for the DELIVER study from AstraZeneca; outside this work, he has received fees for speaking and fees for consultancy from Boehringer Ingelheim, Novartis, Orion Pharma, and Vifor Pharma; and he has received research grants from Novartis, Orion Pharma, and Vifor Pharma. Dr Dobreanu has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Drozdz has received personal and institutional research support for DELIVER from AstraZeneca. Dr Fang has received either personal or institutional research support for DELIVER from AstraZeneca. Dr Gamba has received personal fees from Sanfer, Roche, Amgen, Asofarma, Sanofi, AstraZeneca, Eli Lilly, Boehringer, Bristol Myers Squibb, Bayer, Pfizer, Merck, Abbott, Silanes, Servier, Jansen Cilag, Medtronic, and Boston Scientific. Drs Al Habeeb, Han, Cabrera, Janssens, Vardeny, and Nguyen have received either personal or institutional research support for DELIVER from AstraZeneca. Dr Katova has received fees for serving as national coordinator from Novartis and AstraZeneca. Dr Kitakaze has received support for the present manuscript (funding, provision of study materials, medical writing, article processing charges, etc) from AstraZeneca, has received grants or contracts from the Japanese government through the Japan Agency for Medical Research and Development Japan Heart Foundation, and has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from AstraZeneca, Ono, Novartis, Tanabe-Mitsubishi, Japan Medical Data Center, Takeda, Pfizer, Daiichi-Sankyo, Otsuka, Sanofi, Boehringer Ingelheim, Amgen, Kowa, Toyama-Kagaku, Kureha, Viatris, and Mochida. Dr Merkely has received personal fees from AstraZeneca and Servier. Dr O’Meara has served as a consultant and speaker for AstraZeneca, Bayer, Boehringer Ingelheim, and Novartis; has served as a steering committee member or a national lead investigator with contracts between her institution (Montreal Heart Institute Research Center) and American Regent, AstraZeneca, Cytokinetics, Merck, and Novartis; and has ongoing clinical trial participation with Amgen, Abbott, American Regent, AstraZeneca, Bayer, Boehringer Ingelheim, Cytokinetics, Eidos, Novartis, Merck, Pfizer, and Sanofi. Dr Kerr Saraiva has received research grant support from Pfizer, Daichii Sankyo, Sanofi, Boehringer Ingelheim, Novo Nordisk, AstraZeneca, Janssen, Amgen, and Novartis; and has received honorarium from Boehringer Ingelheim, Novo Nordisk, Astra Zeneca, and Amgen. Dr Tereshchenko has received personal fees from Servier, AstraZeneca, Pfizer, Novartis, and Boehringer Ingelheim. Dr Thierer has received support for lectures and advisory boards from AstraZeneca, Boehringer Ingelheim, and Pfizer. Dr Verma has received research grants and/or speaking honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, EOCI Pharmacomm Ltd, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals, and the Toronto Knowledge Translation Working Group; and is the President of the Canadian Medical and Surgical Knowledge Translation Research Group, a federally incorporated not-for-profit physician organization. Drs Wilderäng, Zaozerska, Lindholm, and Petersson are employees and shareholders of AstraZeneca. Dr McMurray has received funding to his institution, Glasgow University, for his work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Cardurion, Cytokinetics, GlaxoSmithKline, Novartis, Pfizer, and Theracos; and has received personal lecture fees from the Corpus, Abbott, Hickma, Sun Pharmaceuticals, and Medsca., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The sodium-glucose cotransporter 2 inhibitor empagliflozin reduces the risk of cardiovascular death or heart failure hospitalization in patients with chronic heart failure, but whether empagliflozin also improves clinical outcomes when initiated in patients who are hospitalized for acute heart failure is unknown. In this double-blind trial (EMPULSE; NCT04157751 ), 530 patients with a primary diagnosis of acute de novo or decompensated chronic heart failure regardless of left ventricular ejection fraction were randomly assigned to receive empagliflozin 10 mg once daily or placebo. Patients were randomized in-hospital when clinically stable (median time from hospital admission to randomization, 3 days) and were treated for up to 90 days. The primary outcome of the trial was clinical benefit, defined as a hierarchical composite of death from any cause, number of heart failure events and time to first heart failure event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. More patients treated with empagliflozin had clinical benefit compared with placebo (stratified win ratio, 1.36; 95% confidence interval, 1.09-1.68; P = 0.0054), meeting the primary endpoint. Clinical benefit was observed for both acute de novo and decompensated chronic heart failure and was observed regardless of ejection fraction or the presence or absence of diabetes. Empagliflozin was well tolerated; serious adverse events were reported in 32.3% and 43.6% of the empagliflozin- and placebo-treated patients, respectively. These findings indicate that initiation of empagliflozin in patients hospitalized for acute heart failure is well tolerated and results in significant clinical benefit in the 90 days after starting treatment., (© 2022. The Author(s).)

Background: The general objective of the study was to reflect on the key factors to advance in optimal models of care for Heart Failure (HF) and specifically, on the macromanagement elements most necessary for the development of comprehensive HF management models., Material and Methods: An Advisory Committee, composed of 15 experts and a multidisciplinary group of 31 additional experts, was appointed, together forming a Delphi panel of 46 experts. Based on a systematic bibliographic review and the analysis of the care course of the patient with HF, an initial battery of key factors for the development of HF care models was identified by the Advisory Committee. This proposal was adjusted and prioritized by the Delphi panel applying Delphi Rand/UCLA methodology., Results: After two Delphi rounds, 75 key factors grouped into 7 challenges were defined. In the first of the challenges, related to the development of HF management models, 16 key factors were identified, 7 of which were valued as high priority and related to the establishment of common objectives, resources for the continuity of care and improving the measurement of health outcomes., Conclusions: The definition of management elements at the macro level was considered a priority to advance in the development of optimal models of assistance to HF., (Copyright © 2021 FECA. Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: The Impella pump has emerged as a promising tool in patients with cardiogenic shock (CS). Despite its attractive properties, there are scarce data on the specific clinical setting and the potential role of Impella devices in CS patients from routine clinical practice., Methods: This is an observational, retrospective, single center, cohort study. All consecutive patients with diagnosis of CS and undergoing support with Impella 2.5 ® , Impella CP ® or Impella 5.0 ® from April 2015 to December 2020 were included. Baseline characteristics, management and outcomes were assessed according to CS severity, age and cause of CS. Main outcome measured was in-hospital mortality., Results: A total of 50 patients were included (median age: 59.3 ± 10 years). The most common cause of CS was acute coronary syndrome (ACS) (68%), followed by decompensation of previous cardiomyopathy (22%). A total of 13 patients (26%) had profound CS. Most patients (54%) improved pulmonary congestion at 48 h after Impella support. A total of 19 patients (38%) presented significant bleeding. In-hospital mortality was 42%. Among patients with profound CS ( n = 13), five patients were previously supported with venoarterial extracorporeal membrane oxygenation. A total of eight patients (61.5%) died during the admission, and no patient achieved ventricular recovery. Older patients (≥ 67 years, n = 10) had more comorbidities and the highest mortality (70%). Among patients with ACS ( n = 34), 35.3% of patients had profound CS; and in most cases (52.9%), Impella support was performed as a bridge to recovery. In contrast, only one patient from the decompensated cardiomyopathy group ( n = 11) presented with profound CS. In 90.9% of these cases, Impella support was used as a bridge to cardiac transplantation. There were no cases of death., Conclusions: In this cohort of real-life CS patients, Impella devices were used in different settings, with different clinical profiles and management. Despite a significant rate of complications, mortality was acceptable and lower than those observed in other series., (Copyright and License information: Journal of Geriatric Cardiology 2022.)

Introduction: The ESC recently classified European countries into 4 cardiovascular risk regions. However, whether Europeans from higher-risk countries living in lower-risk regions may benefit from intensive cardiovascular prevention efforts is unknown. We described the burden of risk factors and cardiovascular disease (CVD) among European-born immigrants living in Catalonia, a low-risk region., Material and Methods: A retrospective cohort study of 5.6 million adults of European origin living in Catalonia in 2019, including 282,789 European-born immigrants, was performed. We used the regionwide healthcare database and classified participants into 5 groups: low-, moderate-, high-, and very high-risk, and local-born. Age-standardized prevalence was estimated as of December 31 st , 2019 and incidence was computed during 2019 among at-risk individuals., Results: The very high-risk group was the largest immigrant group ( N = 136,910; 48.4%), while the high-risk group was the smallest ( N = 15,739; 5.6%). These two had the highest burden of coronary heart disease across all groups evaluated, in both men and women. The very high-risk group also had the highest prevalence of hypertension and obesity at young-to-middle age, and the burden of risk factors newly diagnosed during 2019 was highest in high- and very high-risk participants. The mean age at first diagnosis of risk factors and CVD was lower in these groups., Conclusions: In Catalonia, residents born in high- and very-high-risk European countries are at increased risk of coronary heart disease and newly diagnosed risk factors. Low-risk European countries may consider tailored prevention efforts, early screening of risk factors, and adequate healthcare resource planning to better address the health needs of men and women from higher-risk countries., Competing Interests: The authors declare no conflict of interest., (Copyright: © 2021 Termedia & Banach.)

Objectives: To gather insights on the disease experience of patients with heart failure (HF) with reduced ejection fraction (HFrEF), and assess how patients' experiences and narratives related to the disease complement data collected through standardised patient-reported outcome measures (PROMs). Also, to explore new ways of evaluating the burden experienced by patients and caregivers., Design: Observational, descriptive, multicentre, cross-sectional, mixed-methods study., Setting: Secondary care, patient's homes., Participants: Twenty patients with HFrEF (New York Heart Association (NYHA) classification I-III) aged 38-85 years., Measures: PROMs EuroQoL 5D-5L (EQ-5D-5L) and Kansas City Cardiomyopathy Questionnaire and patient interview and observation., Results: A total of 20 patients with HFrEF participated in the study. The patients' mean (SD) age was 72.5 (11.4) years, 65% were male and were classified inNYHA functional classes I (n=4), II (n=7) and III (n=9). The study showed a strong impact of HF in the patients' quality of life (QoL) and disease experience, as revealed by the standardised PROMs (EQ-5D-5L global index=0.64 (0.36); Kansas City Cardiomyopathy Questionnaire total symptom score=71.56 (20.55)) and the in-depth interviews. Patients and caregivers often disagreed describing and evaluating perceived QoL, as patients downplayed their limitations and caregivers overemphasised the poor QoL of the patients. Patients related current QoL to distant life experiences or to critical moments in their disease, such as hospitalisations. Anxiety over the disease progression is apparent in both patients and caregivers, suggesting that caregiver-specific tools should be developed., Conclusions: PROMs are an effective way of assessing symptoms over the most recent time period. However, especially in chronic diseases such as HFrEF, PROM scores could be complemented with additional tools to gain a better understanding of the patient's status. New PROMs designed to evaluate and compare specific points in the life of the patient could be clinically more useful to assess changes in health status., Competing Interests: Competing interests: JC-C received fees from AstraZeneca for the coordination and oversight of the study. RR, MFE and SCC received research funding from AstraZeneca. RFdlF, BP and LV are employees of AstraZeneca. All other authors report no competing interests., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Comorbidity burden has been identified as a relevant predictor of critical illness in patients hospitalized with coronavirus disease 2019 (COVID-19). However, comorbidity burden is often represented by a simple count of few conditions that may not fully capture patients' complexity., Purpose: To evaluate the performance of a comprehensive index of the comorbidity burden (Queralt DxS), which includes all chronic conditions present on admission, as an adjustment variable in models for predicting critical illness in hospitalized COVID-19 patients and compare it with two broadly used measures of comorbidity., Materials and Methods: We analyzed data from all COVID-19 hospitalizations reported in eight public hospitals in Catalonia (North-East Spain) between June 15 and December 8 2020. The primary outcome was a composite of critical illness that included the need for invasive mechanical ventilation, transfer to ICU, or in-hospital death. Predictors including age, sex, and comorbidities present on admission measured using three indices: the Charlson index, the Elixhauser index, and the Queralt DxS index for comorbidities on admission. The performance of different fitted models was compared using various indicators, including the area under the receiver operating characteristics curve (AUROCC)., Results: Our analysis included 4607 hospitalized COVID-19 patients. Of them, 1315 experienced critical illness. Comorbidities significantly contributed to predicting the outcome in all summary indices used. AUC (95% CI) for prediction of critical illness was 0.641 (0.624-0.660) for the Charlson index, 0.665 (0.645-0.681) for the Elixhauser index, and 0.787 (0.773-0.801) for the Queralt DxS index. Other metrics of model performance also showed Queralt DxS being consistently superior to the other indices., Conclusion: In our analysis, the ability of comorbidity indices to predict critical illness in hospitalized COVID-19 patients increased with their exhaustivity. The comprehensive Queralt DxS index may improve the accuracy of predictive models for resource allocation and clinical decision-making in the hospital setting., Competing Interests: David Monterde declares that he is the developer of the Queralt System. This tool is available online for research purposes at no cost. The authors report no other conflicts of interest in this work, which did not receive specific funding., (© 2021 Monterde et al.)

Background Early generation drug-eluting stents (DESs) showed a high grade of coronary endothelial dysfunction that was attributed to lack of stent reendothelialization. Endothelium-dependent vasomotor response of current DESs and bioresorbable scaffolds (BRSs) remains unknown. This study sought to assess the device-related endothelial function of current devices and to correlate neointima healing with endothelial function. Methods and Results A total of 206 patients from 4 randomized trials treated with the durable-polymer everolimus-eluting Xience (n=44), bioresorbable-polymer sirolimus-eluting Orsiro (n=35), polymer-free biolimus-eluting Biofreedom (n=24), bioactive endothelial-progenitor cell-capturing sirolimus-eluting Combo DES (n=25), polymer-based everolimus-eluting Absorb (n=44), and Mg-based sirolimus-eluting Magmaris BRS (n=34) underwent endothelium-dependent vasomotor tests and optical coherence tomography imaging, as per protocol, at follow-up. Crude vasomotor responses of distal segments to low-dose acetylcholine (10 -6  mol/L) were different between groups: bioresorbablepolymer DEShad the worst (-8.4%±12.6%) and durable-polymer DES had the most physiologic (-0.4%±11.8%; P =0.014). High-dose acetylcholine (10 -4  mol/L) showed similar responses between groups (ranging from -10.8%±11.6% to -18.1%±15.4%; P =0.229). Device healing was different between devices. Uncovered struts ranged from 6.3%±7.1% (bioresorbable-polymer DES) to 2.5%±4.5% (bioactive DES; P =0.056). In multivariate models, endothelium-dependent vasomotor response was associated with age, bioresorbable-polymer DES, and angiographic lumen loss, but not with strut coverage nor plaque type. Endothelial dysfunction (defined as ≥4% vasoconstriction) was observed in 46.6% of patients with low-dose and 68.9% with high-dose acetylcholine, without differences between groups. Conclusions At follow-up, endothelial dysfunction was frequently observed in distal segments treated with current stents without remarkable differences between devices. Although neointima healing was different between devices, poor healing was not associated with endothelial dysfunction.

Aims: Patients with heart failure (HF) and iron deficiency experience poor health-related quality of life (HRQoL). We evaluated the impact of intravenous (IV) ferric carboxymaltose (FCM) vs. placebo on HRQoL for the AFFIRM-AHF population., Methods and Results: The baseline 12-item Kansas City Cardiomyopathy Questionnaire (KCCQ-12), which was completed for 1058 (535 and 523) patients in the FCM and placebo groups, respectively, was administered prior to randomization and at Weeks 2, 4, 6, 12, 24, 36, and 52. The baseline KCCQ-12 overall summary score (OSS) mean ± standard error was 38.7 ± 0.9 (FCM group) and 37.1 ± 0.8 (placebo group); corresponding values for the clinical summary score (CSS) were 40.9 ± 0.9 and 40.1 ± 0.9. At Week 2, changes in OSS and CSS were similar for FCM and placebo. From Week 4 to Week 24, patients assigned to FCM had significantly greater improvements in OSS and CSS scores vs. placebo [adjusted mean difference (95% confidence interval, CI) at Week 4: 2.9 (0.5-5.3, P = 0.018) for OSS and 2.8 (0.3-5.3, P = 0.029) for CSS; adjusted mean difference (95% CI) at Week 24: 3.0 (0.3-5.6, P = 0.028) for OSS and 2.9 (0.2-5.6, P = 0.035) for CSS]. At Week 52, the treatment effect had attenuated but remained in favour of FCM., Conclusion: In iron-deficient patients with HF and left ventricular ejection fraction <50% who had stabilized after an episode of acute HF, treatment with IV FCM, compared with placebo, results in clinically meaningful beneficial effects on HRQoL as early as 4 weeks after treatment initiation, lasting up to Week 24., (© The Author(s) 2021. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Objective: The RHO family of GTPases, particularly RAC1, has been linked with hepatocarcinogenesis, suggesting that their inhibition might be a rational therapeutic approach. We aimed to identify and target deregulated RHO family members in human hepatocellular carcinoma (HCC)., Design: We studied expression deregulation, clinical prognosis and transcription programmes relevant to HCC using public datasets. The therapeutic potential of RAC1 inhibitors in HCC was study in vitro and in vivo. RNA-Seq analysis and their correlation with the three different HCC datasets were used to characterise the underlying mechanism on RAC1 inhibition. The therapeutic effect of RAC1 inhibition on liver fibrosis was evaluated., Results: Among the RHO family of GTPases we observed that RAC1 is upregulated, correlates with poor patient survival, and is strongly linked with a prooncogenic transcriptional programme. From a panel of novel RAC1 inhibitors studied, 1D-142 was able to induce apoptosis and cell cycle arrest in HCC cells, displaying a stronger effect in highly proliferative cells. Partial rescue of the RAC1-related oncogenic transcriptional programme was obtained on RAC1 inhibition by 1D-142 in HCC. Most importantly, the RAC1 inhibitor 1D-142 strongly reduce tumour growth and intrahepatic metastasis in HCC mice models. Additionally, 1D-142 decreases hepatic stellate cell activation and exerts an anti-fibrotic effect in vivo., Conclusions: The bioinformatics analysis of the HCC datasets, allows identifying RAC1 as a new therapeutic target for HCC. The targeted inhibition of RAC1 by 1D-142 resulted in a potent antitumoural effect in highly proliferative HCC established in fibrotic livers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Risk stratification for ventricular arrhythmias (VA) and sudden death in nonischemic dilated cardiomyopathy (DCM) remains suboptimal., Objectives: The goal of this study was to provide an improved risk stratification algorithm for VA and sudden death in DCM., Methods: This was a retrospective cohort study of consecutive patients with DCM who underwent cardiac magnetic resonance with late gadolinium enhancement (LGE) at 2 tertiary referral centers. The combined arrhythmic endpoint included appropriate implantable cardioverter-defibrillator therapies, sustained ventricular tachycardia, resuscitated cardiac arrest, and sudden death., Results: In 1,165 patients with a median follow-up of 36 months, LGE was an independent and strong predictor of the arrhythmic endpoint (hazard ratio: 9.7; p < 0.001). This association was consistent across all strata of left ventricular ejection fraction (LVEF). Epicardial LGE, transmural LGE, and combined septal and free-wall LGE were all associated with heightened risk. A simple algorithm combining LGE and 3 LVEF strata (i.e., ≤20%, 21% to 35%, >35%) was significantly superior to LVEF with the 35% cutoff (Harrell's C statistic: 0.8 vs. 0.69; area under the curve: 0.82 vs. 0.7; p < 0.001) and reclassified the arrhythmic risk of 34% of patients with DCM. LGE-negative patients with LVEF 21% to 35% had low risk (annual event rate 0.7%), whereas those with high-risk LGE distributions and LVEF >35% had significantly higher risk (annual event rate 3%; p = 0.007)., Conclusions: In a large cohort of patients with DCM, LGE was found to be a significant, consistent, and strong predictor of VA or sudden death. Specific high-risk LGE distributions were identified. A new clinical algorithm integrating LGE and LVEF significantly improved the risk stratification for VA and sudden death, with relevant implications for implantable cardioverter-defibrillator allocation., 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 © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: Iron deficiency (ID) is frequent in heart failure (HF), linked with exercise intolerance and poor prognosis. Intravenous iron repletion improves clinical status in HF patients with left ventricular ejection fraction (LVEF) ≤45%. However, uncertainty exists about the accuracy of serum biomarkers in diagnosing ID. The aims of this study were (i) to identify the iron biomarker with the greatest accuracy for the diagnosis of ID in bone marrow in patients with ischaemic HF, and (ii) to establish the prevalence of ID using this biomarker and its prognostic value in HF patients., Methods and Results: Bone marrow was stained for iron in 30 patients with ischaemic HF with LVEF ≤45% and 10 healthy controls, and ID was diagnosed for 0-1 grades (Gale scale). A total of 791 patients with HF with LVEF ≤45% were prospectively followed up for 3 years. Serum ferritin, transferrin saturation, soluble transferrin receptor (sTfR) were assessed as iron biomarkers. Most patients with HF (n = 25, 83%) had ID in bone marrow, but none of the controls (P < 0.001). Serum sTfR had the best accuracy in predicting ID in bone marrow (area under the curve 0.920, 95% confidence interval 0.761-0.987, for cut-off 1.25 mg/L sensitivity 84%, specificity 100%). Serum sTfR was ≥1.25 mg/L in 47% of HF patients, in 56% and 46% of anaemics and non-anaemics, respectively (P < 0.05). The reclassification methods revealed that serum sTfR significantly added the prognostic value to the baseline prognostic model, and to the greater extent than plasma N-terminal pro B-type natriuretic peptide. Based on internal derivation and validation procedures, serum sTfR ≥1.41 mg/L was the optimal threshold for predicting 3-year mortality, independent of other established variables., Conclusions: High serum sTfR accurately reflects depleted iron stores in bone marrow in patients with HF, and identifies those with a high 3-year mortality., (© 2020 European Society of Cardiology.)

Telemedicine (TM) is potentially a way of escalating heart failure (HF) multidisciplinary integrated care. Despite the initial efforts to implement TM in HF management, we are still at an early stage of its implementation. The coronavirus disease 2019 pandemic led to an increased utilisation of TM. This tendency will probably remain after the resolution of this threat. Face-to-face medical interventions are gradually transitioning to the virtual setting by using TM. TM can improve healthcare accessibility and overcome geographic inequalities. It promotes healthcare system efficiency gains, and improves patient self-management and empowerment. In cooperation with human intervention, artificial intelligence can enhance TM by helping to deal with the complexities of multicomorbidity management in HF, and will play a relevant role towards a personalised HF patient approach. Artificial intelligence-powered/telemedical/heart team/multidisciplinary integrated care may be the next step of HF management. In this review, the authors analyse TM trends in the management of HF patients and foresee its future challenges within the scope of HF multidisciplinary integrated care., Competing Interests: Funding: This article was supported by national funds through Fundação para a Ciência e a Tecnologia, within CINTESIS, R&D Unit (UIDB/4255/2020) and Project ‘AdHeart – Engage with your heart: Improving therapeutic adherence with a telemonitoring system for chronic heart failure patients,’ NORTE-01-0145-FEDER-032069, financed by European Regional Development Fund (ERDF) through NORTE 2020 (Programa Operacional Regional do Norte) and by Portuguese funds through Fundação para a Ciência e Tecnologia. Disclosure: The authors have no conflicts of interest to declare., (Copyright © 2021, Radcliffe Cardiology.)

Aims: Cardiogenic shock (CS) is associated with high mortality. Current guidelines strongly recommend centralizing the care of these patients in high-complexity centres. We described the hospitalization-related economic cost and its main determinants in patients with CS in a high-complexity reference centre., Methods and Results: This is a single-centre, retrospective study. All patients with CS (2015-17) were included. Hospitalization-related cost per patient was calculated by analytical accountability method, including hospital stay-related expenditures, interventions, and consumption of devices. Expenditure was expressed in 2018 euros. All-cause mortality during follow-up was registered. Ratio of cost per life-year gained (LYG) was also calculated. A total of 230 patients were included, with mean age of 63 years. In-hospital mortality was 88/230 (38.3%). Hospital stay was longer in patients surviving after the admission (21.7 vs. 7.5 days, P < 0.001). Total economic cost for the overall cohort was 3 947 118€ (mean/patient 17 161€). Most of this cost was attributable to hospital stay (81.1%). The rest of the expenditure was due to in-hospital procedures (13.1%) and the use of devices (5.8%). Most of hospital stay-related costs (79.8%) were due to Critical Care Unit stay. Mean follow-up was 651 days. Total LYG was 409.77 years for the whole series. The observed ratio of cost per LYG was 9632.52 €/LYG., Conclusions: Management of CS in a reference centre is associated to a significant economic cost, but with a low ratio of cost per LYG. Most of this cost is attributable to hospital stay, specifically in critical care units., (Published on behalf of the European Society of Cardiology VC © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: OUTSTEP-HF compared the effect of sacubitril/valsartan vs. enalapril on 6-min walk test (6MWT) distance, non-sedentary daytime physical activity and heart failure (HF) symptoms in patients with HF with reduced ejection fraction (HFrEF)., Methods and Results: Ambulatory patients (n = 621) with stable symptomatic HFrEF were randomised 1:1 to sacubitril/valsartan (n = 310) or enalapril (n = 311). Changes in physical activity and mean daily non-sedentary daytime activity from baseline to Week 12 were measured using 6MWT and a wrist-worn accelerometer device, respectively. After 12 weeks, 6MWT improved by 35.09 m with sacubitril/valsartan [97.5% confidence interval (CI) 27.85, 42.32] and by 26.11 m with enalapril (97.5% CI 18.78, 33.43); however, there was no significant difference between groups [least squares means treatment difference: 8.98 m (97.5% CI -1.31, 19.27); P = 0.0503]. Mean daily non-sedentary daytime activity decreased by 27 min with sacubitril/valsartan and by 21 min with enalapril [least squares means treatment difference: -6 min (97.5% CI -25.7, 13.4), P = 0.4769] after 12 weeks. 6MWT improved by ≥30 m in 51% of patients in the sacubitril/valsartan group vs. 44% of patients treated with enalapril (odds ratio 1.251, 95% CI 0.895, 1.748). At Week 4, non-sedentary daytime activity increased by ≥10% in 58% of patients treated with sacubitril/valsartan vs. 64% with enalapril; 58% of patients treated with sacubitril/valsartan reported improved HF symptoms as assessed by patient global assessment vs. 43% with enalapril. However, these differences did not persist at Week 12., Conclusion: After 12 weeks of treatment, there was no significant benefit of sacubitril/valsartan on either 6MWT or daytime physical activity measured by actigraphy compared with enalapril., (© 2020 European Society of Cardiology.)

Background: Intravenous ferric carboxymaltose has been shown to improve symptoms and quality of life in patients with chronic heart failure and iron deficiency. We aimed to evaluate the effect of ferric carboxymaltose, compared with placebo, on outcomes in patients who were stabilised after an episode of acute heart failure., Methods: AFFIRM-AHF was a multicentre, double-blind, randomised trial done at 121 sites in Europe, South America, and Singapore. Eligible patients were aged 18 years or older, were hospitalised for acute heart failure with concomitant iron deficiency (defined as ferritin <100 μg/L, or 100-299 μg/L with transferrin saturation <20%), and had a left ventricular ejection fraction of less than 50%. Before hospital discharge, participants were randomly assigned (1:1) to receive intravenous ferric carboxymaltose or placebo for up to 24 weeks, dosed according to the extent of iron deficiency. To maintain masking of patients and study personnel, treatments were administered in black syringes by personnel not involved in any study assessments. The primary outcome was a composite of total hospitalisations for heart failure and cardiovascular death up to 52 weeks after randomisation, analysed in all patients who received at least one dose of study treatment and had at least one post-randomisation data point. Secondary outcomes were the composite of total cardiovascular hospitalisations and cardiovascular death; cardiovascular death; total heart failure hospitalisations; time to first heart failure hospitalisation or cardiovascular death; and days lost due to heart failure hospitalisations or cardiovascular death, all evaluated up to 52 weeks after randomisation. Safety was assessed in all patients for whom study treatment was started. A pre-COVID-19 sensitivity analysis on the primary and secondary outcomes was prespecified. This study is registered with ClinicalTrials.gov, NCT02937454, and has now been completed., Findings: Between March 21, 2017, and July 30, 2019, 1525 patients were screened, of whom 1132 patients were randomly assigned to study groups. Study treatment was started in 1110 patients, and 1108 (558 in the carboxymaltose group and 550 in the placebo group) had at least one post-randomisation value. 293 primary events (57·2 per 100 patient-years) occurred in the ferric carboxymaltose group and 372 (72·5 per 100 patient-years) occurred in the placebo group (rate ratio [RR] 0·79, 95% CI 0·62-1·01, p=0·059). 370 total cardiovascular hospitalisations and cardiovascular deaths occurred in the ferric carboxymaltose group and 451 occurred in the placebo group (RR 0·80, 95% CI 0·64-1·00, p=0·050). There was no difference in cardiovascular death between the two groups (77 [14%] of 558 in the ferric carboxymaltose group vs 78 [14%] in the placebo group; hazard ratio [HR] 0·96, 95% CI 0·70-1·32, p=0·81). 217 total heart failure hospitalisations occurred in the ferric carboxymaltose group and 294 occurred in the placebo group (RR 0·74; 95% CI 0·58-0·94, p=0·013). The composite of first heart failure hospitalisation or cardiovascular death occurred in 181 (32%) patients in the ferric carboxymaltose group and 209 (38%) in the placebo group (HR 0·80, 95% CI 0·66-0·98, p=0·030). Fewer days were lost due to heart failure hospitalisations and cardiovascular death for patients assigned to ferric carboxymaltose compared with placebo (369 days per 100 patient-years vs 548 days per 100 patient-years; RR 0·67, 95% CI 0·47-0·97, p=0·035). Serious adverse events occurred in 250 (45%) of 559 patients in the ferric carboxymaltose group and 282 (51%) of 551 patients in the placebo group., Interpretation: In patients with iron deficiency, a left ventricular ejection fraction of less than 50%, and who were stabilised after an episode of acute heart failure, treatment with ferric carboxymaltose was safe and reduced the risk of heart failure hospitalisations, with no apparent effect on the risk of cardiovascular death., Funding: Vifor Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objectives: To assess the characteristics and risk factors for mortality in patients with severe coronavirus disease-2019 (COVID-19) treated with tocilizumab (TCZ), alone or in combination with corticosteroids (CS)., Methods: From March 17 to April 7, 2020, a real-world observational retrospective analysis of consecutive hospitalized adult patients receiving TCZ to treat severe COVID-19 was conducted at our 750-bed university hospital. The main outcome was all-cause in-hospital mortality., Results: A total of 1,092 patients with COVID-19 were admitted during the study period. Of them, 186 (17%) were treated with TCZ, of which 129 (87.8%) in combination with CS. Of the total 186 patients, 155 (83.3 %) patients were receiving noninvasive ventilation when TCZ was initiated. Mean time from symptoms onset and hospital admission to TCZ use was 12 (±4.3) and 4.3 days (±3.4), respectively. Overall, 147 (79%) survived and 39 (21%) died. By multivariate analysis, mortality was associated with older age (HR = 1.09, p < 0.001), chronic heart failure (HR = 4.4, p = 0.003), and chronic liver disease (HR = 4.69, p = 0.004). The use of CS, in combination with TCZ, was identified as a protective factor against mortality (HR = 0.26, p < 0.001) in such severe COVID-19 patients receiving TCZ. No serious superinfections were observed after a 30-day follow-up., Conclusions: In patients with severe COVID-19 receiving TCZ due to systemic host-immune inflammatory response syndrome, the use of CS in addition to TCZ therapy, showed a beneficial effect in preventing in-hospital mortality., (Copyright © 2020 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Introduction: Patients with heart failure (HF) display elevated levels of soluble fractalkine, a chemokine involved in inflammation processes, atherosclerosis and platelet activation. Further, fractalkine has been associated with reduced pharmacodynamic (PD) responsiveness to clopidogrel. The aim of this study was to investigate the association of fractalkine with the severity of HF and its impact on platelet activation and clopidogrel response in patients with coronary artery disease (CAD) with and without HF., Materials and Methods: This prospective PD study included 116 stable CAD patients on DAPT with aspirin and clopidogrel. Subjects were classified in two groups: patients with HF and reduced (<40%) left ventricular ejection fraction (HFrEF group, n = 56) and patients without HF (no HF group, n = 60). Clinical severity of HF was graded according to NYHA classification. Platelet function assays included vasodilator-stimulated phosphoprotein assay, multiple electrode aggregometry and light transmittance aggregometry. Fractalkine and P-selectin concentrations were determined by ELISA., Results: Fractalkine levels progressively increased with the severity of the disease in the HFrEF group (NYHA I: 471.2 ± 52.4 pg/ml, NYHA II: 500.5 ± 38.4 pg/ml, NYHA III: 638.9 ± 54.3 pg/ml, p for linear trend 0.023). Numerically higher concentrations of fractalkine were observed in the HFrEF group compared to the no HF group with borderline significance (p = 0.052). No significant differences in clopidogrel-induced platelet inhibition according to fractalkine values were observed in any of the groups., Conclusions: Fractalkine levels were increased in patients with HFrEF and positively associated with the functional severity of the disease. No evident impact of fractalkine on clopidogrel PD efficacy was found., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Sympathetic activity (SA) is increased in patients with heart failure and reduced ejection fraction (HFrEF) and is associated with poor outcomes. However, its clinical implications are less understood in HF with mid-range (HFmrEF) and preserved ejection fraction (HFpEF). We aimed to study SA across left ventricle ejection fraction (LVEF) groups and its association with clinical outcomes., Methods and Results: SA estimated by norepinephrine (NE) levels was determined in 742 consecutive outpatients with chronic HF: 348 (47%) with HFrEF, 116 (16%) HFmrEF, and 278 (37%) HFpEF. After a mean follow-up of 15 months, 17% died. Adjusted analyses showed that patients with HFpEF and HFmrEF had lower estimated marginal means of NE levels compared to HFrEF (278 and 116 pg/mL, respectively, vs. 348 pg/mL; p-value=0.005). Adjusted Cox regression analyses showed that high norepinephrine levels independently predicted all-cause mortality (ACM) in all 3 groups. The strongest associations between high NE levels and cardiovascular mortality (CVM) were observed in HFmrEF (HR: 4.7 [1.33-16.68]), while the weakest association was in HFpEF (HR: 2.62 [1.08-6.35])., Conclusions: Adjusted analyses showed that HFpEF and HFmrEF were associated with lower SA compared to HFrEF. Nevertheless, increasing NE levels were independently associated with ACM and CVM in all three LVEF groups. The strongest association between high NE levels and CVM was present in HFmrEF patients, while the weakest was seen in HFpEF. These findings could explain why the response to neurohormonal therapies in patients with HFmrEF is similar to that of patients with HFrEF rather than with HFpEF., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Introduction and Objectives: Treatment with intravenous iron in patients with heart failure (HF) and iron deficiency (ID) improves symptoms, however its impact on survival and safety is unknown. We aimed to evaluate the management of ID and anemia with intravenous iron in patients with HF and long-term safety of intravenous iron., Methods: We evaluated anemia and ID in patients with chronic HF at 3 university hospitals. Anemia was defined using the World Health Organization definition and ID was defined as ferritin <100 ug/L or a Transferrin Saturation <20% if ferritin between 100 and 299 ug/L. We assessed treatment with intravenous iron during follow-up and its association with mortality and HF hospitalizations using multivariate cox regression analysis., Results: We included 2,114 patients, median age 72 years and 57% had reduced left ventricular ejection fraction. ID was present in 55% and ID and anemia in 29%. Treatment with intravenous iron was used in 24% of patients with ID and 34% of patients with ID and anemia. In patients with ID, after multivariate adjustment, treatment with intravenous iron was associated with lower all-cause mortality: HR = 0.38 (0.28-0.56), lower cardiovascular mortality: HR = 0.34 (0.20-0.57) and no differences in HF hospitalizations: HR = 1.15 (0.88-1.50). Similar outcomes were found for patients with anemia and ID., Conclusions: In a real-world cohort of patients with HF, treatment with intravenous iron was used in one third of patients with ID and anemia and appears safe in mid-term follow-up., Competing Interests: Declaration of Competing Interest JCC has received speaking fees from Vifor Pharma and was a member of the steering committee of the FAIR-HF and CONFIRM-HF studies. None of the other authors have any conflicts of interest., (Copyright © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Background: In patients with heart failure, chronic kidney disease is common and associated with a higher risk of renal events than in patients without chronic kidney disease. We assessed the renal effects of angiotensin/neprilysin inhibition in patients who have heart failure with preserved ejection fraction enrolled in the PARAGON-HF trial (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction)., Methods: In this randomized, double-blind, event-driven trial, we assigned 4822 patients who had heart failure with preserved ejection fraction to receive sacubitril/valsartan (n=2419) or valsartan (n=2403). Herein, we present the results of the prespecified renal composite outcome (time to first occurrence of either: ≥50% reduction in estimated glomerular filtration rate (eGFR), end-stage renal disease, or death from renal causes), the individual components of this composite, and the influence of therapy on eGFR slope., Results: At randomization, eGFR was 63±19 mL·min -1 ·1.73 m - 2. At study closure, the composite renal outcome occurred in 33 patients (1.4%) assigned to sacubitril/valsartan and 64 patients (2.7%) assigned to valsartan (hazard ratio, 0.50 [95% CI, 0.33-0.77]; P =0.001). The treatment effect on the composite renal end point did not differ according to the baseline eGFR (<60 versus ≥60 mL·min -1 ·1.73 m -2 ( P -interaction=0.92). The decline in eGFR was less for sacubitril/valsartan than for valsartan (-2.0 [95% CI, -2.2 to -1.9] versus -2.7 [95% CI, -2.8 to -2.5] mL·min -1 ·1.73 m -2 per year)., Conclusions: In patients with heart failure with preserved ejection fraction, sacubitril/valsartan reduced the risk of renal events, and slowed decline in eGFR, in comparison with valsartan. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01920711.

Background: The aims of the present analysis are to estimate the prevalence of five key chronic cardiovascular, metabolic and renal conditions at the population level, the prevalence of renin-angiotensin-aldosterone system inhibitor (RAASI) medication use and the magnitude of potassium (K + ) derangements among RAASI users., Methods and Results: We used data from more than 375,000 individuals, 55 years of age or older, included in the population-based healthcare database of the Catalan Institute of Health between 2015 and 2017. The conditions of interest were chronic heart failure (CHF), chronic kidney disease (CKD), diabetes mellitus, ischemic heart disease and hypertension. RAASI medications included angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, mineralocorticoid receptor antagonists (MRAs) and renin inhibitors. Hyperkalemia was defined as K + levels >5.0 mEq/L and hypokalemia as K + <3.5 mEq/L. The prevalence of chronic cardiovascular, metabolic and renal conditions was high, and particularly that of hypertension (prevalence ranging from 48.2% to 48.9%). The use of at least one RAASI medication was almost ubiquitous in these patients (75.2-77.3%). Among RAASI users, the frequency of K + derangements, mainly of hyperkalemia, was very noticeable (12% overall), particularly in patients with CKD or CHF, elderly individuals and users of MRAs. Hypokalemia was less frequent (1%)., Conclusion: The high prevalence of K + derangements, and particularly hyperkalemia, among RAASI users highlights the real-world relevance of K + derangements, and the importance of close monitoring and management of K + levels in routine clinical practice. This is likely to benefit a large number of patients, particularly those at higher risk., Competing Interests: Josep Comin-Colet had received speaker fees from Vifor Pharma. The authors report no other potential conflicts of interest for this work., (© 2020 Jiménez-Marrero et al.)

Aim: In PARADIGM-HF, sacubitril/valsartan demonstrated superiority to enalapril in reducing mortality and morbidity in patients with heart failure (HF) with reduced ejection fraction (HFrEF). Several patient-centred outcomes like improved physical activity and quality of life have been emphasised as important treatment goals in HF management. OUTSTEP-HF has been designed to evaluate the effect of sacubitril/valsartan compared with enalapril on non-sedentary daytime physical activity in patients with HFrEF., Methods: OUTSTEP-HF is a randomised, actively controlled, double-blind, double-dummy study that plans to enrol 600 ambulatory patients with symptomatic HFrEF in 19 European countries. Patients will be randomised 1:1 to receive sacubitril/valsartan 97/103 mg bid or enalapril 10 mg bid. The primary objective of the study is to assess changes from baseline (Week 0) to Week 12 in exercise capacity measured by the 6-min walk test and in daily non-sedentary daytime activity. Physical activity and objective sleep parameters will be measured by accelerometry using a wrist-worn device, worn continuously from screening (Week -2) until the end of study (Week 12). As a co-primary outcome, changes from baseline in sub-maximal exercise capacity will be assessed by the 6-min walk test. Patient- and physician-reported questionnaires will be used to assess quality of life, changes in signs and symptoms of HF and sleep parameters., Conclusion: OUTSTEP-HF will be the largest randomised trial in HF to date to use non-invasive accelerometry to assess whether treatment with sacubitril/valsartan improves patients' daily physical activity and exercise capacity compared with enalapril., (© 2020 European Society of Cardiology.)

Introduction: Nurses play an important part in the education of patients with HF. To prepare patients with HF for self-care maintenance behaviours, nurses must have knowledge of basic self-care maintenance principles., Aim Study: The aim of this study was to determine the degree of knowledge of primary care (PC) nurses on the principles of self-management of HF and variables associated with this., Methodology: This is an observational, cross-sectional descriptive study, carried out in 2014, in the city of Barcelona (Catalonia). Nurses' Knowledge of Heart Failure Education Principles questionnaire (NKHFEP) was used to assess the principles of HF self-care education. Instrument items assess knowledge of nurses on 5 themes: diet, liquids/weight, worsening signs or symptoms, medication and exercise. Factors related to adequate knowledge were evaluated., Results: Of 216 PC nurses, who completed the questionnaire, the average score was 15.6 (SD: 2.2). Only 36 (16.7%) obtained an adequate level of knowledge and defined as a score ≥ 18 points. In multivariate logistic regression, nurse factors associated with an adequate knowledge of principles of self-care of HF were having achieved a PhD degree (OR: 36.4, 95% CI: 2.8-468.2, p = 0.006) and previous specific training in HF (OR: 19.8, 95% CI: 1.4-279.3, p = 0.026)., Conclusions: The degree of knowledge of PC nurses in the principles of self-care in HF was higher among nurses who had completed the doctorate and in nurses who had received specific training in HF., (© 2019 Nordic College of Caring Science.)

Levosimendan was first approved for clinic use in 2000, when authorisation was granted by Swedish regulatory authorities for the haemodynamic stabilisation of patients with acutely decompensated chronic heart failure. In the ensuing 20 years, this distinctive inodilator, which enhances cardiac contractility through calcium sensitisation and promotes vasodilatation through the opening of adenosine triphosphate-dependent potassium channels on vascular smooth muscle cells, has been approved in more than 60 jurisdictions, including most of the countries of the European Union and Latin America. Areas of clinical application have expanded considerably and now include cardiogenic shock, takotsubo cardiomyopathy, advanced heart failure, right ventricular failure and pulmonary hypertension, cardiac surgery, critical care and emergency medicine. Levosimendan is currently in active clinical evaluation in the US. Levosimendan in IV formulation is being used as a research tool in the exploration of a wide range of cardiac and non-cardiac disease states. A levosimendan oral form is at present under evaluation in the management of amyotrophic lateral sclerosis. To mark the 20 years since the advent of levosimendan in clinical use, 51 experts from 23 European countries (Austria, Belgium, Croatia, Cyprus, Czech Republic, Estonia, Finland, France, Germany, Greece, Hungary, Italy, the Netherlands, Norway, Poland, Portugal, Russia, Slovenia, Spain, Sweden, Switzerland, UK and Ukraine) contributed to this essay, which evaluates one of the relatively few drugs to have been successfully introduced into the acute heart failure arena in recent times and charts a possible development trajectory for the next 20 years., Competing Interests: Disclosure: PP, TS and MK are full- or part-time employees of Orion Pharma. In the past 5 years, all other authors have received honoraria from Orion Pharma for educational lectures and/or unrestricted grants for investigator-initiated studies., (Copyright © 2020, Radcliffe Cardiology.)

This paper describes the application of whole-genome sequencing (WGS) to investigate an outbreak of Mycobacterium tuberculosis occurring in Aragon, Spain, where strains have been submitted to genotyping since 2004. The responsible outbreak strain appeared in our region first in 2014 and it spread to 14 patients in the following three years. WGS found low variability between the isolates with none of the SNPs differences detected more than once, all of which were attributed to a recent transmission. Although two ambiguous bases linked two cases with those who presented the SNP in the same position, the establishment of a definitive transmission route was not possible. The epidemiological data supported the existence of a super-spreader, probably responsible for the majority of the cases involved since there was a two-year delay in diagnoses among cases. This fact would also help explaining the low variability found. The index case was not identified, possibly because it was not diagnosed in Aragon. In addition WGS characterised the strain as a Linage 4.3.3/LAM family and corroborated the susceptibility to anti-tuberculosis drugs observed by the clinical laboratories. This work shows the need to have epidemiological data to support the genomic data in order to clarify the evolution of tuberculosis outbreaks., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Aims: While the associations of health-related quality of life scores in heart failure (HF) [e.g. the Kansas City Cardiomyopathy Questionnaire (KCCQ)] with clinical outcomes are well established, their interpretation in the context of what magnitudes of change are clinically important to patients is less clear. The main objective of this study was to correlate the changes in the KCCQ and Patient Global Assessment (PGA) in patients with HF with reduced ejection fraction (HFrEF) to determine minimal clinically important difference (MCID)., Methods and Results: We analysed data from 459 patients of the FAIR-HF trial. Both KCCQ and PGA were assessed at 4 and 24 weeks after enrolment. An anchor-based approach was used to calculate MCID at week 4 and 24. PGA was chosen as the clinical anchor against which changes in the KCCQ scores were calibrated. For each category of change in PGA, the corresponding differences were calculated by the mean scores of various domains of KCCQ along with 95% confidence intervals (CIs). There was fair correlation between PGA and changes in overall summary scores (OSS) (r = 0.31; P < 0.001), clinical summary scores (CSS) (r = 0.36; P < 0.001) and physical limitation scores (PLS) (r = 0.31; P < 0.001) from baseline to week 4. KCCQ OSS, CSS and PLS MCID for 'little improvement' at week 4 were 3.6 (1.0-6.2), 4.5 (1.8-7.2) and 4.7 (1.4-8.0) points, respectively. OSS, CSS and PLS MCID for 'little improvement' at week 24 were 4.3 (0.2-8.4), 4.5 (0.5-8.5) and 4.0 (-0.9-9.0) points, respectively., Conclusion: The MCID threshold for KCCQ score was generally consistent and numerically lower than the threshold of 5-point change considered for clinical outcome prognosis and were stable between 4 and 24 weeks. This suggests that even changes smaller than the traditional 5-point improvements in KCCQ may be clinically meaningful. Also, these results can aid in the clinical interpretation of patient-reported outcomes, and better endpoint selection in future studies., (© 2020 European Society of Cardiology.)

Iron deficiency and iron-deficiency anemia are associated with increased morbidity and mortality in a wide range of conditions. In many patient populations, this can be treated effectively with oral iron supplementation; but in patients who are unable to take or who do not respond to oral iron therapy, intravenous iron administration is recommended. Furthermore, in certain conditions, such as end-stage kidney disease, chronic heart failure, and inflammatory bowel disease, intravenous iron administration has become first-line treatment. One of the first available intravenous iron preparations is iron sucrose (Venofer ® ), a nanomedicine that has been used clinically since 1949. Treatment with iron sucrose is particularly beneficial owing to its ability to rapidly increase hemoglobin, ferritin, and transferrin saturation levels, with an acceptable safety profile. Recently, important new data relating to the use of iron sucrose, including the findings from the landmark PIVOTAL trial in patients with end-stage kidney disease, have been reported. Several years ago, a number of iron sucrose similars became available, although there have been concerns about the clinical appropriateness of substituting the original iron sucrose with an iron sucrose similar because of differences in efficacy and safety. This is a result of the complex and unique physicochemical properties of nanomedicines such as iron sucrose, which make copying the molecule difficult and problematic. In this review, we summarize the evidence accumulated during 70 years of clinical experience with iron sucrose in terms of efficacy, safety, and cost-effectiveness.

Circadian rhythm is essential for cellular regulation of physiological, metabolic, and immune functions. Perturbations of circadian rhythms have been correlated with increased susceptibility to cancer and poor prognosis in the cancer treatment. Our aim is to investigate the role of doxorubicin (DOX) treatment on clock genes expression and inflammation in intraperitoneal macrophages and the antitumoral response., Methods: Macrophages were extracted from intraperitoneal cavity of mice without or with Lewis lung carcinoma (LLC) and treated with DOX totaling four groups (CTL, LLC, LLC+DOX and DOX) and analyzes of clock genes in six time points (ZT02, ZT06, ZT10, ZT14, ZT18 AND ZT22). Intraperitoneal macrophages cell culture was stimulated with LPS and DOX and clock genes and inflammatory profile were analyzed. In tumor were analyzed macrophages markers., Results: The expression of F4/80 (ZT22) and CD11c (ZT06) tumor tissue was significantly differed between LLC and LCC+DOX groups. In the intraperitoneal macrophages, DOX increased Clock (ZT10), Rev-Erbα (ZT18 and ZT22) and Per2 expressions (ZT18); in the LLC+DOX group was increased Bmal1 (ZT10), Per2 (ZT18) and NF-kB (ZT22) expressions; IL-6 expression increased in the LCC group (ZT02). In intraperitoneal macrophages cell culture stimulated with DOX and LPS after 24 h decreased Clock and Per1. DOX causes depression after 6 and 24 h in TNF-α content and Per2 gene expression after 24 h IL-1β expression was reduced also., Conclusion: DOX treatment in vivo disrupted cytokine and clock genes expression in intraperitoneal macrophages suppressing immune response. Moreover, macrophages cultured with DOX had decreased expression of LPS-stimulated inflammatory cytokines.

Background: Accurate risk adjustment is crucial for healthcare management and benchmarking., Purpose: We aimed to compare the performance of classic comorbidity functions (Charlson's and Elixhauser's), of the All Patients Refined Diagnosis Related Groups (APR-DRG), and of the Queralt Indices, a family of novel, comprehensive comorbidity indices for the prediction of key clinical outcomes in hospitalized patients., Material and Methods: We conducted an observational, retrospective cohort study using administrative healthcare data from 156,459 hospital discharges in Catalonia (Spain) during 2018. Study outcomes were in-hospital death, long hospital stay, and intensive care unit (ICU) stay. We evaluated the performance of the following indices: Charlson's and Elixhauser's functions, Queralt's Index for secondary hospital discharge diagnoses (Queralt DxS), the overall Queralt's Index, which includes pre-existing comorbidities, in-hospital complications, and principal discharge diagnosis (Queralt Dx), and the APR-DRG. Discriminative ability was evaluated using the area under the curve (AUC), and measures of goodness of fit were also computed. Subgroup analyses were conducted by principal discharge diagnosis, by age, and type of admission., Results: Queralt DxS provided relevant risk adjustment information in a larger number of patients compared to Charlson's and Elixhauser's functions, and outperformed both for the prediction of the 3 study outcomes. Queralt Dx also outperformed Charlson's and Elixhauser's indices, and yielded superior predictive ability and goodness of fit compared to APR-DRG (AUC for in-hospital death 0.95 for Queralt Dx, 0.77-0.93 for all other indices; for ICU stay 0.84 for Queralt Dx, 0.73-0.83 for all other indices). The performance of Queralt DxS was at least as good as that of the APR-DRG in most principal discharge diagnosis subgroups., Conclusion: Our findings suggest that risk adjustment should go beyond pre-existing comorbidities and include principal discharge diagnoses and in-hospital complications. Validation of comprehensive risk adjustment tools such as the Queralt indices in other settings is needed., Competing Interests: David Monterde declares that he is the developer of a software tool that can be used to compute the Queralt Index in clinical, management and research settings. The tool is available online at no cost. Dr Josep Comin-Colet reports grants, personal fees, non-financial support from Vifor Pharma, grants, personal fees from Novartis, grants, personal fees, non-financial support from Orion Pharma, outside the submitted work. The authors declare that they have no other conflicts of interest relevant to the content of this manuscript., (© 2020 Monterde et al.)

Inotropes aim at increasing cardiac output by enhancing cardiac contractility. They constitute the third pharmacological pillar in the treatment of patients with decompensated heart failure, the other two being diuretics and vasodilators. Three classes of parenterally administered inotropes are currently indicated for decompensated heart failure, (i) the beta adrenergic agonists, including dopamine and dobutamine and also the catecholamines epinephrine and norepinephrine, (ii) the phosphodiesterase III inhibitor milrinone and (iii) the calcium sensitizer levosimendan. These three families of drugs share some pharmacologic traits, but differ profoundly in many of their pleiotropic effects. Identifying the patients in need of inotropic support and selecting the proper inotrope in each case remain challenging. The present consensus, derived by a panel meeting of experts from 21 countries, aims at addressing this very issue in the setting of both acute and advanced heart failure., (Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.)

In 2018, cardiovascular disease (CVD) was the leading cause of death among women, and current CVD prevention paradigms may not be sufficient in this group. In that context, it has recently been proposed that detection of calcification in breast arteries may help improve CVD risk screening and assessment in apparently healthy women. This review provides an overview of breast arterial anatomy; and the epidemiology, pathophysiology, and measurement of breast artery calcium (BAC); and discusses the features of the BAC-CVD link. The potential clinical applications that BAC may offer for CVD prevention in the context of current clinical practice guidelines and recommendations are also discussed. Finally, current gaps in evidence gaps are outlined, and future directions in the field are explored with a focus on the implementation of BAC mammography as a CVD risk-screening tool in routine clinical practice., (Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)