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Worsening heart failure (HF) is a vulnerable period in which the patient has a markedly high risk of death or HF hospitalization (up to 10% and 30%, respectively, within the first weeks after episode). The prognosis of HF patients can be improved through a comprehensive approach that considers the different neurohormonal systems, with the early introduction and optimization of the quadruple therapy with sacubitril-valsartan, beta-blockers, mineralocorticoid receptor antagonists, and inhibitors. Despite that, there is a residual risk that is not targeted with these therapies. Currently, it is recognized that the cyclic guanosine monophosphate deficiency has a negative direct impact on the pathogenesis of HF, and vericiguat, an oral stimulator of soluble guanylate cyclase, can restore this pathway. The effect of vericiguat has been explored in the VICTORIA study, the largest chronic HF clinical trial that has mainly focused on patients with recent worsening HF, evidencing a significant 10% risk reduction of the primary composite endpoint of cardiovascular death or HF hospitalization (number needed to treat 24), after adding vericiguat to standard therapy. This benefit was independent of background HF therapy. Therefore, optimization of treatment should be performed as earlier as possible, particularly within vulnerable periods, considering also the use of vericiguat., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: There is little information about the influence of gender on quality of life (QoL) in heart failure. The purpose of this study was to evaluate whether the health-related QoL gap between men and women can be explained by the interaction between psychosocial factors and clinical determinants in a real-word cohort of patients with chronic heart failure., Methods and Results: We conducted a single-centre, observational, prospective cohort study of 1236 consecutive patients diagnosed with chronic heart failure recruited between 2004 and 2014. To assess QoL, we used the Minnesota Living with Heart Failure Questionnaire (MLHFQ). Female gender was associated with worse global QoL compared to male gender (MLHFQ overall summary score: 49 ± 23 vs. 43 ± 24; P value <0.001, respectively) and similarly had poorer scores in physical and emotional dimensions but scored better on social dimension. In univariate models and in models adjusted for clinical determinants, female gender behaved as a predictor of worse global, physical and emotional QoL, and better social QoL compared with men. In models only including psychosocial determinants and in comprehensive models including all psychosocial and clinical factors, these differences according to gender were no longer significant., Conclusions: In this study, we have shown that the gap in health-related QoL between men and women with chronic heart failure can be partially explained by the interaction between biological and psychosocial factors. Biological factors are the main drivers of QoL in HF patients. However, the contribution of psychosocial factors is essential to definitively understand the role of gender in this field., (© 2022 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background and Aims: Heart failure (HF) programs successfully reduce 30-day readmissions. However, conflicting data exist about its sustained effects afterwards and its impact on mortality. We evaluated whether the impact of a new nurse-led coordinated transitional HF program extends to longer periods of time, including 90 and 180 days after discharge., Methods and Results: We designed a natural experiment to undertake a pragmatical evaluation of the implementation of the program. We compared outcomes between patients discharged with HF as primary diagnosis in Period #1 (pre-program; Jan 2017-Aug 2017) and those discharged during Period #2 (HF program; Sept 2017-Jan 2019). Primary endpoint was the composite of all-cause death or all-cause hospitalization 90 and 180 days after discharge. 440 patients were enrolled: 123 in Period #1 and 317 in Period #2. Mean age was 75±9 years. There were more females in Period #2 (p = 0.025), with no other significant differences between periods. The primary endpoint was significantly reduced in the HF program group, at 90 [adjusted OR 0.31 (0.18-0.53), p <0.001] and at 180 days [adjusted OR 0.18 (CI 0.11-0.32), p <0.001]. Such a decrease was due to a reduction in cardiovascular (CV) and HF hospitalization. All-cause death was reduced when a double check discharge planning was implanted compared to usual care [0 (0%) vs. 7 (3.8%), p = 0.022]., Conclusion: A new nurse-led coordinated transitional bundle of interventions model reduces the composite endpoint of all-cause death and all-cause hospitalization both at 90 and 180 days after a discharge for HF, also in high-risk populations. Such a decrease is driven by a reduction of CV and HF hospitalization. Reduction of all-cause mortality was also observed when the full model including a more exhaustive discharge planning process was implemented., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Alcoberro et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: The potential positive effect of electronic health (eHealth)-based heart failure (HF) monitoring remains uncertain mainly in the 'low literacy' or 'computer or digital illiterate' patients. The aim of this study was to determine the effectiveness of a telemedicine (TM)-based managed care solution across literacy levels and information and communications technology (ICT) skills., Methods: We performed a sub-analysis on the basis of two literacy domains encompassed in the definition of 'eHealth literacy' to the HF-patients included in the 'insuficiència Cardíaca Optimització Remota' (iCOR) randomized study comparing TM vs. usual care (UC) in HF-patients. The primary study endpoint was the incidence of a non-fatal HF event after 6 months of inclusion. The event rates of primary and secondary study endpoints were calculated for each literacy domains and its combination. Cox proportional-hazards regression models were used to evaluate the effect of 'eHealth literacy' dimensions, treatment group and the interaction term 'eHealth literacy' domains by treatment group on study endpoints., Results: The beneficial effect of TM compared to UC strategy was consistent across all literacy domains (p-value for interaction 0.207 and 0.117 respectively). The risk of experiencing a primary event was significantly lower in patients that underwent allocation to the TM arm compared to UC in both clustered in the 'lower literacy' (p-value=0.001) and those allocated to the 'lower ICT skills' (p-value=0.001) subgroup., Conclusions: Non-invasive eHealth-based HF monitoring tools are effective compared to UC in preventing HF events in the early post-discharge period, regardless of two 'eHealth literacy' domains ('traditional and computer literacy')., (Copyright © 2022. Published by Elsevier B.V.)

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.)

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.)

Background: The potential impact of telemedicine (TM) in the monitoring of patients with heart failure (HF) is still uncertain particularly in the frailest patients. The aim of this study was to define the efficacy of a TM-based managed care solution across different HF patient frailty phenotypes., Methods: We performed a clustering analysis on the basis of 8 frailty-related dimensions to the HF-patients included in the 'insuficiència Cardíaca Optimització Remota' (iCOR) randomised study comparing TM vs. usual care (UC) in HF patients. The primary study endpoint was the incidence of a non-fatal HF event after 6 months of inclusion. The healthcare-related costs in each study group and cluster were also evaluated. The event rates of primary and secondary study endpoints were calculated for each cluster. Cox proportional-hazards regression models were used to evaluate the effect of cluster, treatment group and the interaction term cluster by treatment group on study endpoints., Results: 5 different frailty phenotypes were identified. The positive effect of TM compared to UC strategy was consistent across all frailty phenotypes (p-value for interaction 0.711). The risk of experiencing a primary event was significantly lower in patients that underwent allocation to the TM arm compared to UC (p-value = 0.016). Ultimately, the healthcare costs were significantly reduced in patients allocated to the TM compared to UC in all 5 frailty phenotypes (all p-value < 0.05)., Conclusions: Non-invasive TM-based follow-up tools are effective compared to UC follow-up in preventing HF events in the early post-discharge period, regardless of the 5 frailty phenotypes., (Copyright © 2021. Published by Elsevier B.V.)

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.)

Aims: In ambulatory patients with chronic heart failure (HF), congestion and decongestion assessment may be challenging. The aim of this study is to assess the value of lung ultrasound (LUS) in outpatients with HF in characterizing decompensation and recompensation, and in outcomes prediction., Methods and Results: Heart failure outpatients attended to establish HF decompensation were included. LUS was blindly performed at baseline (LUS1) and at clinical recompensation (LUS2). B-lines were counted in eight scanned areas. Diagnosis of no HF decompensation vs. right-sided, left-sided, or global HF decompensation, and patients' management were performed by physicians blinded to LUS1. Outcome was the composite of all-cause death or HF-related hospitalization. Two hundred and thirty-three suspicions of HF decompensation were included in 187 patients (71.4 ± 11.3 years, 66.8% men). Mean B-line (LUS1) was 17.6 ± 11.2 vs. 3.7 ± 4.5 for episodes with and without HF decompensation, respectively (P < 0.001). Global HF decompensation showed the highest number of B-lines (20.6 ± 11), followed by left-sided (19.7 ± 11.6) and right-sided (13.5 ± 9.8). B-lines declined to 6.9 ± 6.7 (LUS2) (P < 0.001 vs. LUS1) after treatment, within a mean time of 24.2 ± 23.7 days [median 13.5 days (interquartile range 6-40)]. B-lines were significantly associated with the composite endpoint at 30 days (hazard ratio [HR] 1.04 [95% confidence interval 1.01-1.07], P = 0.02), but not at 60 (P = 0.22) or 180 days (P = 0.54). In multivariable analysis, B-line number remained as an independent predictor of the composite endpoint at 30 days, [HR 1.04 (1.01-1.07), P = 0.014], with a 4% increase risk per B-line added. B-lines correlated significantly with CA125 (R = 0.30, P = 0.001)., Conclusions: Lung ultrasound supports the diagnostic work-up of congestion and decongestion in chronic HF outpatients and identifies patients at high risk of short-term events., (© 2021 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Abnormal endogenous erythropoietin (EPO) constitutes an important cause of anaemia in chronic diseases. We analysed the relationships between iron deficiency (ID) and the adequacy of endogenous EPO in anaemic heart failure (HF) patients, and the impact of abnormal EPO on 12-month mortality., Methods and Results: We investigated 435 anaemic HF patients (age: 74 ± 10 years; males: 60%; New York Heart Association class I or II: 39%; left ventricular ejection fraction: 43 ± 17%). Patients with EPO higher than expected for a given haemoglobin were considered EPO-resistant whereas those with EPO lower than expected - EPO-deficient. ID was defined as serum ferritin <100 µg/L or 100-299 µg/L with transferrin saturation <20%. EPO-resistant patients (22%) had more advanced HF whereas those with EPO deficiency (57%) were more frequently females and had worse renal function. Lower serum ferritin (indicating depleted body iron stores) was related to higher EPO observed/predicted ratio when adjusted for significant clinical confounders, including C-reactive protein. One year all-cause mortality was 28% in patients with EPO resistance compared to 17% in patients with EPO deficiency and 10% in patients with adequate EPO (log-rank test for the comparison EPO resistance vs. adequate EPO: P = 0.02). When adjusted for other prognosticators, there was still a trend towards increased 12-month mortality in patients with higher EPO level., Conclusion: Anaemic HF patients with endogenous EPO deficiency vs. resistance have different clinical and laboratory characteristics. In such patients, ID contributes to EPO resistance independently of inflammation., (© 2021 European Society of Cardiology.)

Introduction and Objectives: The role of lung ultrasound (LUS) in acute heart failure (HF) has been widely studied, but little is known about its usefulness in chronic HF. This study assessed the prognostic value of LUS in a cohort of chronic HF stable ambulatory patients., Methods: We included consecutive outpatients who attended a scheduled follow-up visit in a HF clinic. LUS was performed in situ. The operators were blinded to clinical data and examined 8 thoracic areas. The sum of B-lines across all lung zones and the quartiles of this addition were used for the analyses. Linear regression and Cox regression analyses were performed. The main clinical outcomes were a composite of all-cause death or hospitalization for HF and mortality from any cause., Results: A total of 577 individuals were included (72% men; 69± 12 years). The mean number of B-lines was 5±6. During a mean follow-up of 31±7 months, 157 patients experienced the main clinical outcome and 111 died. Having ≥ 8 B-lines (Q4) doubled the risk of experiencing the composite primary event (P <.001) and increased the risk of death from any cause by 2.6-fold (P <.001). On multivariate analysis, the total sum of B-lines remained independent predictive factor of the composite endpoint (HR, 1.04; 95%CI, 1.02-1.06; P=.002) and of all-cause death (HR, 1.04; 95%CI, 1.02-1.07; P=.001), independently of whether or not N-terminal pro-B-type natriuretic peptide (NT-proBNP) was included in the model (P=.01 and P=.008, respectively), with a 3% to 4% increased risk for each 1-line addition., Conclusions: LUS identified patients with stable chronic HF at high risk of death or HF hospitalization., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: Potassium derangements are frequent among patients with chronic cardiovascular conditions. Studies on the associations between potassium derangements and clinical outcomes have yielded mixed findings, and the implications for health care expenditure are unknown. We assessed the population-based associations between hyperkalemia, hypokalemia and clinical outcomes and health care costs, in patients with chronic heart failure, chronic kidney disease, diabetes mellitus, hypertension, and ischemic heart disease., Methods: Population-based, longitudinal study including up to 36 269 patients from a health care area with at least one of the above-mentioned conditions. We used administrative, hospital and primary care databases. Participants were followed up between 2015 and 2017, were aged ≥ 55 years and had at least 1 potassium measurement. Four analytic designs were used to evaluate prevalent and incident cases and the use of renin-angiotensin-aldosterone system inhibitors., Results: Hyperkalemia was twice as frequent as hypokalemia. On multivariable-adjusted analyses, hyperkalemia was robustly and significantly associated with an increased risk of all-cause death (HR from Cox regression models ranging from 1.31-1.68) and with an increased odds of a yearly health care expenditure >85th percentile (OR, 1.21-1.29). Associations were even stronger in hypokalemic patients (HR for all-cause death, 1.92-2.60; OR for health care expenditure> percentile 85th, 1.81-1.85)., Conclusions: Experimental studies are needed to confirm whether the prevention of potassium derangements reduces mortality and health care expenditure in these chronic conditions. Until then, our findings provide observational evidence on the potential importance of maintaining normal potassium levels., (Copyright © 2020 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. 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.)

Background & Aims: Nutritional status is an important prognostic factor in patients with heart failure (HF). In a pilot study we previously observed that the Mini Nutritional Assessment Short Form tool (MNA-SF) was the best approach for the screening of nutritional status in HF outpatients over other screening tools. The current study aimed to determine whether the MNA-SF has prognostic value in outpatients with HF and whether the impact of malnutrition differs depending on left ventricular ejection fraction (LVEF)., Methods: Prospective study performed in outpatients attending a HF clinic at a university hospital. All subjects completed the MNA-SF at study entry. The primary endpoint was all-cause mortality. Secondary end-points were the number of recurrent HF-related hospitalizations and the composite end-point of all-cause death or HF-related hospitalizations. Patients with malnutrition and at risk of malnutrition were merged and considered as having abnormal nutritional status for statistical analysis., Results: From October 2016 to November 2017, 555 patients were included (age 69 ± 11.5 years, 71% male, LVEF 44.6 ± 13.2). Abnormal nutritional status was identified in 103 (18.6%) subjects. HF patients with preserved LVEF had a higher proportion of abnormal nutritional status (23%) than patients with HF and mid-range LVEF (HFmrEF) (16.4%) or those with HF with reduced LVEF (HFrEF) (15.9%.). During a mean follow-up of 23.8 ± 6.6 months, 99 patients died (17.8%), 74 were hospitalized due to HF (13.3%) and the composite end-point was observed in 181 (32.6%). In the univariate analysis, abnormal nutritional status was significantly associated with all-cause mortality (p = 0.02) and the composite end-point (p = 0.02) in the total cohort. However, in the multivariate analysis including age, sex, NYHA functional class, BMI, ischemic aetiology, diabetes, hypertension and HF duration, abnormal nutritional status remained significantly associated with all-cause mortality (HR 3.32 [95%CI 1.47-7.52], p = 0.004), and the composite end-point (HR 2.53 [95%CI 1.30-4.94], p = 0.006) only in HFmrEF patients. Patients with abnormal nutritional status suffered double the crude number of recurrent HF-related hospitalizations (16.4 vs. 8.4 per 100 patients-years, p < 0.001)., Conclusions: The implementation of MNA-SF as a routine screening tool allowed the detection of abnormal nutritional status in almost one out of five ambulatory HF patients. Nutritional status assessed by the MNA-SF was an independent predictor of all-cause death and the composite end-point of all-cause death or HF-related hospitalization in outpatients with HFmrEF. Furthermore, abnormal nutritional status was significantly related to recurrent hospitalizations across the HF spectrum., (Copyright © 2020 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Aims: Systolic pulmonary artery pressure (SPAP), tricuspid annular plane systolic excursion (TAPSE), and TAPSE/SPAP ratio trajectories are not fully characterized in chronic heart failure (HF). We assessed very long-term longitudinal SPAP, TAPSE and TAPSE/SPAP trajectories in HF patients, and their dynamic changes in outcomes., Methods and Results: Prospective, consecutive, observational registry of real-life HF patients, performing echocardiography studies at baseline and according to a prospectively structured schedule after 1 year, and then every 2 years, up to 15 years. Pulmonary hypertension (PH) was defined as SPAP ≥40 mmHg; right ventricular dysfunction (RVD) was defined at TAPSE ≤16 mm; and TAPSE/SPAP ratio was dichotomized at 0.36 mm/mmHg. The clinical endpoints were all-cause death, the composite endpoint of mortality or HF hospitalization and the number of recurrent HF hospitalizations. The study cohort included 1557 patients. Long-term SPAP trajectory Loess curves were U-shaped with a nadir at 7 years. TAPSE Loess curves showed a marked rise during the first year, with stabilization thereafter. TAPSE/SPAP ratio Loess splines were similar to the later with a smooth decline towards the end. Patients who died had higher SPAP, lower TAPSE and lower TAPSE/SPAP ratio in the preceding period than survivors. Baseline PH and/or RVD were independently associated with mortality and HF-related hospitalizations, and the persistence of one or both entities at 1 year conferred a worse long-term prognosis., Conclusions: Long-term trajectories for SPAP, TAPSE and TAPSE/SPAP ratio are reported in patients with chronic HF. An increasing SPAP and declining TAPSE and TAPSE/SPAP ratio in the preceding period is associated with higher mortality., (© 2020 European Society of Cardiology.)

Aims: Current guidelines recommend sacubitril/valsartan for patients with heart failure and reduced left ventricular ejection fraction (LVEF), but there is lack of evidence of its efficacy and safety in cancer therapy-related cardiac dysfunction (CTRCD). Our aim was to analyse the potential benefit of sacubitril/valsartan in patients with CTRCD., Methods and Results: We performed a retrospective multicentre registry (HF-COH) in six Spanish hospitals with cardio-oncology clinics including all patients treated with sacubitril/valsartan. Demographic and clinical characteristics and laboratory and echocardiographic data were collected. Median follow-up was 4.6 [1; 11] months. Sixty-seven patients were included (median age was 63 ± 14 years; 64% were female, 87% had at least one cardiovascular risk factor). Median time from anti-cancer therapy to CTRD was 41 [10; 141] months. Breast cancer (45%) and lymphoma (39%) were the most frequent neoplasm, 31% had metastatic disease, and all patients were treated with combination antitumor therapy (70% with anthracyclines). Thirty-nine per cent of patients had received thoracic radiotherapy. Baseline median LVEF was 33 [27; 37], and 21% had atrial fibrillation. Eighty-five per cent were on beta-blocker therapy and 76% on mineralocorticoid receptor antagonists; 90% of the patients were symptomatic NYHA functional class ≥II. Maximal sacubitril/valsartan titration dose was achieved in 8% of patients (50 mg b.i.d.: 60%; 100 mg b.i.d.: 32%). Sacubitril/valsartan was discontinued in four patients (6%). Baseline N-terminal pro-B-type natriuretic peptide levels (1552 pg/mL [692; 3624] vs. 776 [339; 1458]), functional class (2.2 ± 0.6 vs. 1.6 ± 0.6), and LVEF (33% [27; 37] vs. 42 [35; 50]) improved at the end of follow-up (all P values ≤0.01). No significant statistical differences were found in creatinine (0.9 mg/dL [0.7; 1.1] vs. 0.9 [0.7; 1.1]; P = 0.055) or potassium serum levels (4.5 mg/dL [4.1; 4.8] vs. 4.5 [4.2; 4.8]; P = 0.5). Clinical, echocardiographic, and biochemical improvements were found regardless of the achieved sacubitril-valsartan dose (low or medium/high doses)., Conclusions: Our experience suggests that sacubitril/valsartan is well tolerated and improves echocardiographic functional and structural parameters, N-terminal pro-B-type natriuretic peptide levels, and symptomatic status in patients with CTRCD., (© 2020 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Background: Left ventricular ejection fraction (LVEF) trajectories and functional recovery with current heart failure (HF) management is increasingly recognized. Type 2 diabetes mellitus (T2D) leads to a worse prognosis in HF patients. However, it is unknown whether T2D interferes with LVEF trajectories. The aim of this study was to prospectively assess very long-term (up to 15 years) LVEF trajectories in patients with and without T2D and underlying HF., Methods: Ambulatory patients admitted to a multidisciplinary HF clinic were prospectively evaluated by scheduled two-dimensional echocardiography at baseline, 1 year, and then every 2 years afterwards, up to 15 years. Statistical analyses of LVEF change with time were performed using the linear mixed effects (LME) models, and locally weighted error sum of squares (Loess) curves were plotted., Results: Of the 1921 patients, 461 diabetic and 699 non-diabetic patients with LVEF < 50% were included in the study. The mean number of echocardiography measurements performed in diabetic patients was 3.3 ± 1.6. Early LVEF recovery was similar in diabetic and non-diabetic patients, but Loess curves showed a more pronounced inverted U shape in diabetics with a more pronounced decline after 9 years. LME analysis showed a statistical interaction between T2D and LVEF trajectory over time (p = 0.009), which was statistically significant in patients with ischemic etiologies (p < 0.001). Other variables that showed an interaction between LVEF trajectories and T2D were male sex (p = 0.04) and HF duration (p = 0.008)., Conclusions: LVEF trajectories in T2D patients with depressed systolic function showed a pronounced inverted U shape with a marked decline after 9 years. Diabetic cardiomyopathy may underlie the functional decline observed.

Background & Aims: There is no consensus on the best method for nutritional screening and assessment in patients with heart failure (HF). This study aimed to determine which nutritional assessment method had the highest prognostic significance for patients with HF treated in outpatient clinics. We also aimed to identify a fast, reliable screening method for detecting malnutrition in these patients., Methods: This prospective study included 151 subjects that attended an outpatient HF clinic at a university hospital. All patients completed three nutritional screening tools: the Malnutrition Universal Screening Tool (MUST), the MNA-short form (MNA-SF), and the Malnutrition Screening Tool (MST), and then, two nutritional assessment questionnaires: the Subjective Global Assessment (SGA) and the Mini Nutritional Assessment®(MNA). Patients were followed-up for 2 years. The primary endpoint was all-cause mortality., Results: Malnutrition or nutritional risk was identified in 15.9% of patients with the SGA and in 25.1% of patients with the MNA. Age, New York Heart Association (NYHA) functional class, and MNA were the only independent all-cause death predictors after adjusting for age, gender, NYHA functional class, body mass index, Barthel index, 25-hydroxyvitamin D concentrations, treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, and treatment with beta-blockers. The SGA could not independently predict all-cause mortality in a multivariate analysis that included the same covariates. The MNA-SF had the best sensitivity, specificity, and kappa coefficient for screening malnutrition, based on the MNA and the SGA as references, compared to the other screening methods., Conclusions: In our cohort, malnutrition assessed by MNA, but not by SGA, was an independent predictor of mortality. MNA-SF showed remarkable sensitivity and specificity; thus, it might be a valuable tool for rapidly identifying malnutrition risk in outpatients with HF., (Copyright © 2018 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Background: Sudden cardiac death (SCD) is one of the main modes of death in heart failure (HF) patients and its prediction remains a real challenge. Our aim was to assess the incidence of SCD at 5 years HF contemporary managed outpatients, and to find a simple prediction model for SCD., Methods: SCD was considered any unexpected death, witnessed or not, occurring in a previously stable patient with no evidence of worsening HF or any other cause of death. A competing risk strategy was adopted using the Fine-Gray method of Cox regressions analyses that considered other causes of death as the competing event., Results: The derivation cohort included 744 consecutive outpatients (72% men, age 67.9 ± 12.2 years, left ventricular ejection fraction [LVEF] 36% ± 14). During follow-up, 312 deaths occurred, 40 SCDs (5.4%). Age, haemoglobin, eGFR, HF duration, high-sensitivity troponin T, NTproBNP, and ST2 were associated with SCD in univariate analyses; HF duration (p = 0.006), eGFR (p < 0.001), LVEF <45% (p = 0.03), and ST2 (p = 0.006) remained in multivariable analysis. A predictive score (ST2-SCD) including dichotomous variables (ST2 > 45, LVEF <45%, HF duration >3 years, eGFR < 55, age ≥ 60 years and male sex) provided a Harrell's C-statistic of 0.82 (0.76-0.89)), reaching 0.87 (0.80-0.95) in the validation cohort (n = 149)., Conclusions: In contemporary managed HF, SCD occurred in 5.4% of outpatients, accounting for 12.8% of all deaths at 5 years. Of the 3 studied biomarkers, only ST2 remained independently associated with SCD. A model containing age, sex, ST2, eGFR, LVEF, and HF duration reasonably predicted 5-years risk of SCD., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aims: Better management of heart failure (HF) over the past two decades has improved survival, mainly by reducing the incidence of death due to cardiovascular (CV) causes. Deaths due to non-CV causes, particularly cancer, may be increasing. This study explored the modes of death of consecutive patients who attended a HF clinic over 17 years., Methods and Results: A total of 935 deaths were ascertained from 2002 to 2018 among 1876 patients (mean age 65.8 ± 12.5 years, 75% men, left ventricular ejection fraction < 50%) admitted to our HF clinic. Median follow-up was 4.2 years [1.9-7.8]. Mode of death was curated from patient health records and verified by the Catalan and Spanish health system databases. Trends for every mode of death were assessed by polynomial regression. Two trends were observed: a significant reduction in sudden death (P = 0.03) without changes in HF progression as mode of death (P = 0.26), and a significant increase in non-CV modes of death (P < 0.001). Non-CV deaths accounted for 17.4% of deaths in 2002 and 65.8% of deaths in 2018. A total 138 deaths were due to cancer (37% of non-CV deaths). A significant trend was observed towards a progressive increase in cancer deaths over time (P = 0.002). The main mode of cancer mortality was lung cancer., Conclusions: The modes of death in HF have shifted over the last two decades. Patients with HF die less due to sudden death and more due to non-CV causes, mainly cancer. Whether HF triggers cancer, or cancer develops in HF survivors, deserves further insight., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Background: Chronic obstructive pulmonary disease and heart failure (HF) are 2 diseases with high morbidity and mortality. The coexistence of these two diseases is estimated to be frequent, but has been poorly studied., Aim: To study the prevalence of airflow limitation in a sample of patients diagnosed with HF in follow-up in an HF unit and to assess their characteristics and comorbidities., Methods: This is a prospective observational study. The patients who visited the HF Unit of the Hospital Universitari Germans Trias i Pujol between January 2014 and June 2015 were included consecutively. Respiratory functional tests were performed and clinical data were obtained., Results: 118 patients were included in the study (age 67.2 years, 77.1% men). The prevalence of non-reversible airflow obstruction was 36.4%, with an underdiagnosis percentage of 67.4%. Patients with airflow limitation had an increase in comorbidities, but no worse prognosis., Conclusion: The prevalence of airflow limitation in patients with HF is high, with a significant degree of underdiagnosis. It seems reasonable to recommend performing a screening spirometry in these patients., (Copyright © 2018 Elsevier España, S.L.U. All rights reserved.)

Background: Long-term trajectories of left ventricular ejection fraction (LVEF) in heart failure (HF) patients with preserved EF (HFpEF) remain unclear. Our objective was to assess long-term longitudinal trajectories in consecutive HFpEF patients and the prognostic impact of LVEF dynamic changes over time., Methods and Results: Consecutive ambulatory HFpEF patients admitted to a multidisciplinary HF Unit were prospectively evaluated by 2-dimensional echocardiography at baseline and at 1, 3, 5, 7, 9, and 11 years of follow-up. Exclusion criteria were patients having a previous known LVEF <50%, patients undergoing only 1 echocardiogram study, and those with a diagnosis of dilated, noncompaction, alcoholic, or toxic cardiomyopathy. One hundred twenty-six patients (age, 71±13 years; 63% women) were included. The main pathogeneses were valvular disease (36%) and hypertension (28%). Atrial fibrillation was present in 67 patients (53%). The mean number of echocardiographies performed was 3±1.2 per patient. Locally weighted error sum of squares curves showed a smooth decrease of LVEF during the 11-year follow-up that was statistically significant in linear mixed-effects modeling ( P=0.01). Ischemic patients showed a higher decrease than nonischemics. The great majority (88.9%) of patients remained in the HFpEF category during follow-up; 9.5% evolved toward HF with midrange LVEF, and only 1.6% dropped to HF with reduced LVEF. No significant relationship was found between LVEF dynamics in the immediate preceding period and mortality., Conclusions: LVEF remained ≥50% in the majority of patients with HFpEF for ≤11 years. Only 1.6% of patients evolved to HF with reduced LVEF. Dynamic LVEF changes were not associated with mortality.

Background Mechanisms underlying iron homeostasis dysregulation in patients with chronic heart failure remain unsettled. In cardiomyocyte models, norepinephrine may lead to intracellular iron depletion, but the potential association between catecholamines (sympathetic activation markers) and iron metabolism biomarkers in chronic heart failure is unknown. Methods and Results In this cross-sectional analysis, we studied the association between plasma norepinephrine levels and serum iron status biomarkers indicating iron storage (ferritin), iron transport (transferrin saturation), and iron demand (soluble transferrin receptor) in a prospective cohort of 742 chronic heart failure patients (mean age, 72±11 years; 56% male). Impaired iron status was defined as ferritin <100 μg/L or transferrin saturation <20%. Impaired iron status was observed in 69% of patients. In multivariate models, greater norepinephrine levels were associated with impaired iron transport (transferrin saturation <20%, odds ratio=2.28; 95% CI [1.19-4.35]; P=0.013), but not with impaired iron storage (ferritin <100 μg/L, odds ratio=1.25; 95% CI [0.73-2.16]; P=0.415). Norepinephrine was a significant predictor of increased iron demand (soluble transferrin receptor, standardized β-coefficient=0.12; P=0.006) and low transferrin saturation (standardized β-coefficient=-0.12; P=0.003). However, norepinephrine levels were not associated with iron or ferritin levels ( P>0.05). Adjusted norepinephrine marginal means were significantly higher in patients with impaired iron status compared with those with normal iron status (528 pg/mL [505-551] versus 482 pg/mL [448-518], respectively; P=0.038). Conclusions In chronic heart failure patients, increased sympathetic activation estimated with norepinephrine levels is associated with impaired iron status and, particularly, dysregulation of biomarkers suggesting impaired iron transport and increased iron demand. Whether the relationship between norepinephrine and iron metabolism is bidirectional and entails causality need to be elucidated in future research.

Aims: Advanced interatrial block (IAB) is characterized by a prolonged (≥120 ms) and bimodal P wave in the inferior leads. The association between advanced IAB and atrial fibrillation (AF) is known as "Bayes' Syndrome", and there is scarce information about it in heart failure (HF). We examined the prevalence of IAB and whether advanced IAB could predict new-onset AF and/or stroke in HF patients., Methods and Results: The prospective observational "Bayes' Syndrome-HF" study included consecutive outpatients with chronic HF. The primary endpoints were new-onset AF, ischemic stroke, and the composite of both. A secondary endpoint included all-cause death alone or in combination with the primary endpoint. Comprehensive multivariable Cox regression analyses were performed. Among 1050 consecutive patients, 536 (51.0%) were in sinus rhythm, 464 with a measurable P wave are the focus of this study. Two-hundred and sixty patients (56.0%) had normal atrial conduction, 95 (20.5%) partial IAB, and 109 (23.5%) advanced IAB. During a mean follow-up of 4.5 ± 2.1 years, 235 patients experienced all-cause death, new-onset AF, or stroke. In multivariable comprehensive Cox regression analyses, advanced IAB was associated with new-onset AF (HR 2.71 [1.61-4.56], P < 0.001), ischemic stroke (HR 3.02 [1.07-8.53], P = 0.04), and the composite of both (HR 2.42 [1.41-4.15], P < 0.001)., Conclusions: In patients with HF advanced IAB predicts new-onset AF and ischemic stroke. Future studies must assess whether anticoagulant treatment in Bayes' Syndrome leads to better outcomes in HF., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Monocytes are a heterogeneous population of effector cells with key roles in tissue integrity restoration and maintenance. Here, we explore the association of monocyte subsets and prognosis in patients with ambulatory heart failure (HF). Monocyte subsets were classified as classical (CD14++/CD16-), intermediate (CD14++/CD16+), or non-classical (CD14+/CD16++). Percentage distribution and absolute cell count were assessed in each subset, and multivariable Cox regression analyses were performed with all-cause death, HF-related hospitalization, and the composite end-point of both as dependent variables. 400 patients were consecutively included (72.8% male, age 69.4±12.2 years, 45.5% from ischemic aetiology, left ventricle ejection fraction (LVEF) 41.6% ±14.5, New York Heart Association (NYHA) class II 62.8% and III 30.8%). During a mean follow-up of 2.6±0.9 years, 107 patients died, 99 had a HF-related hospitalization and 160 suffered the composite end-point of all-cause death or HF-related hospitalization. Monocyte subsets assessed in percentages were not independently associated to any of the end-points. When considering number of cells/μL, intermediate subset was independently associated with an increase of all-cause death (HR 1.25 [95% CI 1,02-1.52], p = 0.03), and the composite end-point HR 1.20 [95% CI 1,03-1.40], p = 0.02). The presented findings show that absolute cell count of monocyte subsets was preferred over monocyte percentage for prognosis stratification for outpatients with HF. The intermediate monocyte subset provides information on increased risk of all-cause death and the composite end-point., Competing Interests: The authors have declared that no competing interests exist.

Background: Long-term trajectories of left ventricular ejection fraction (LVEF) in heart failure (HF) are incompletely characterized., Objectives: This study sought to examine LVEF trajectories in HF with reduced LVEF (<40%) and mid-range LVEF (40% to 49%) and the prognostic impact of LVEF dynamic changes over 15-year follow-up., Methods: In this prospective, consecutive, observational registry of real-life HF outpatients, the authors performed 2-dimensional echocardiography at baseline and on a structured schedule after 1 year and then every 2 years up to 15 years., Results: The mean number of LVEF measurements in the 1,160 included patients was 3.6 ± 1.7. As a whole, Loess curves of long-term LVEF trajectories showed an inverted U shape with a marked rise in LVEF during the first year, maintained up to a decade, and a slow LVEF decline thereafter (p for trajectory <0.001). This pattern was more pronounced in HF of nonischemic origin and in women. Patients with new-onset HF (≤12 months) had a higher early increase in LVEF, whereas patients with ischemic HF showed a lower LVEF increase at 1 year; both groups had a relative plateau thereafter. Patients with HF with mid-range LVEF had less of an increase (3 ± 9%) than those with HF with reduced LVEF (9 ± 12%) during the first year (p < 0.001), but the groups overlapped after 15 years. Patients who died had lower final LVEF and worse LVEF dynamics in the immediately preceding period than survivors., Conclusions: LVEF trajectories vary in HF depending on a number of disease modifiers, but an inverted U-shaped pattern with lower LVEF at both ends of the distribution emerged. A declining LVEF in the preceding period was associated with higher mortality., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Heart failure (HF) is associated with a high rate of readmissions within 30 days post-discharge and in the following year, especially in frail elderly patients. Biomarker data are scarce in this high-risk population. This study assessed the value of early post-discharge circulating levels of ST2, NT-proBNP, CA125, and hs-TnI for predicting 30-day and 1-year outcomes in comorbid frail elderly patients with HF with mainly preserved ejection fraction (HFpEF)., Methods: Blood samples were obtained at the first visit shortly after discharge (4.9 ± 2 days). The primary endpoint was the composite of all-cause mortality or HF-related rehospitalization at 30 days and at 1 year. All-cause mortality alone at one year was also a major endpoint. HF-related rehospitalizations alone were secondary end-points., Results: From February 2014 to November 2016, 522 consecutive patients attending the STOP-HF Clinic were included (57.1% women, age 82 ± 8.7 years, mean Barthel index 70 ± 25, mean Charlson comorbidity index 5.6 ± 2.2). The composite endpoint occurred in 8.6% patients at 30 days and in 38.5% at 1 year. In multivariable analysis, ST2 [hazard ratio (HR) 1.53; 95% CI 1.19-1.97; p = 0.001] was the only predictive biomarker at 30 days; at 1 year, both ST2 (HR 1.34; 95% CI 1.15-1.56; p < 0.001) and NT-proBNP (HR 1.19; 95% CI 1.02-1.40; p = 0.03) remained significant. The addition of ST2 and NT-proBNP into a clinical predictive model increased the AUC from 0.70 to 0.75 at 30 days (p = 0.02) and from 0.71 to 0.74 at 1 year (p < 0.05). For all-cause death at 1 year, ST2 (HR 1.50; 95% CI 1.26-1.80; p < 0.001), and CA125 (HR 1.41; 95% CI 1.21-1.63; p < 0.001) remained independent predictors in multivariable analysis. The addition of ST2 and CA125 into a clinical predictive model increased the AUC from 0.74 to 0.78 (p = 0.03). For HF-related hospitalizations, ST2 was the only predictive biomarker in multivariable analyses, both at 30 days and at 1 year., Conclusions: In a comorbid frail elderly population with HFpEF, ST2 outperformed NT-proBNP for predicting the risk of all-cause mortality or HF-related rehospitalization. ST2, a surrogate marker of inflammation and fibrosis, may be a better predictive marker in high-risk HFpEF.

Background: Recent ESC guidelines on heart failure (HF) have introduced a new phenotype based on left ventricular ejection fraction (LVEF), called the mid-range (HFmrEF). This phenotype falls between the classical reduced (HFrEF) and preserved (HFpEF) HF phenotypes. We aimed to characterize the HFmrEF biomarker profile and outcomes., Methods: 1069 consecutive ambulatory patients were included in the study (age 66.2 ± 12.8 years); 800 with HFrEF (74.8%), 134 with HFmrEF (12.5%), and 135 with HFpEF (12.5%). We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), soluble suppression of tumorigenicity (ST2), galectin-3, high-sensitivity C-reactive protein, cystatin-C, neprilysin, and soluble transferrin receptor, during 4.9 ± 2.8 years of follow-up. The primary end-point was the composite: cardiovascular death or HF-related hospitalization. We also examined all-cause, cardiovascular death, and the composite: all-cause death or HF-related hospitalization., Results: NTproBNP levels in HFmrEF were similar to levels in HFpEF, but significantly lower than levels in HFrEF. No other studied biomarkers were different between HFmrEF and HFrEF. All biomarkers, except neprilysin, showed higher risk prediction capabilities in HFmrEF than in HFrEF or HFpEF. The largest difference between HFrEF and HFmrEF was the hs-TnT level (hazard ratio [HR]: 4.72, 95% CI: 2.81-7.94 vs. HR: 1.67, 95%CI: 1.74-1.89; all p < 0.001)., Conclusions: Although HFmrEF is acknowledged as an intermediate phenotype between HFrEF and HFpEF, from a multi-biomarker point of view, HFmrEF was similar to HFrEF, except that NTproBNP levels were lower. Biomarkers commonly used for HFrEF risk prediction are more valuable for HFmrEF risk stratification., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: Cross-sectional investigations report shorter telomeres in patients with heart failure (HF); however, no studies describe telomere length (TL) trajectory and its relationship with HF progression. Here we aimed to investigate telomere shortening over time and its relationship to outcomes., Methods: Our study cohort included 101 ambulatory patients with HF. Blood samples were collected at baseline (n = 101) and at the 1-year follow-up (n = 54). Using flow-FISH analysis of circulating monocytes, we simultaneously measured three monocyte subsets-classical (CD14 ++ CD16 - ), intermediate (CD14 ++ CD16 + ), and nonclassical (CD14 + CD16 ++ )-and their respective TLs based on FITC-labeled PNA probe hybridization. The primary endpoints were all-cause death and the composite of all-cause death or HF-related hospitalization, assessed at 2.3 ± 0.6 years. All statistical analyses were executed by using the SPSS 15.0 software, and included Student's t test and ANOVA with post hoc Scheffe analysis, Pearson or Spearman rho correlation and univariate Cox regression when applicable., Results: We found high correlations between TL values of different monocyte subsets: CD14 ++ CD16 + vs. CD14 ++ CD16 - , R = 0.95, p < 0.001; CD14 ++ CD16 + vs. CD14 + CD16 ++ , R = 0.90, p < 0.001; and CD14 ++ CD16 - vs. CD14 + CD16 ++ , R = 0.89, p < 0.001. Mean monocyte TL exhibited significant attrition from baseline to the 1-year follow-up (11.1 ± 3.3 vs. 8.3 ± 2.1, p < 0.001). TL did not significantly differ between monocyte subsets at either sampling time-point (all p values > 0.1). Cox regression analyses did not indicate that TL or ΔTL was associated with all-cause death or the composite endpoint., Conclusions: Overall, this longitudinal study demonstrated a ~ 22% reduction of TL in monocytes from ambulatory patients with HF within 1 year. TL and ΔTL were not related to outcomes over long-term follow-up.

Aims: Multidisciplinary heart failure (HF) clinics are a cornerstone of contemporary HF management. The stent-for-life (SFL) initiative improves mortality after ST elevation myocardial infarction (STEMI), but its impact in post-STEMI HF is not well characterized. Here we assessed the impact of SFL among patients referred to a multidisciplinary HF clinic over a 15 year time period., Methods and Results: Between 2001 and 2015, 1921 patients were admitted to our HF clinic. In 2009, Catalonia established the Codi IAM network, a regional STEMI network that prioritizes primary percutaneous coronary intervention in STEMI. Patients admitted during the study period were divided into two groups based on admission date: pre-SFL (2001-June 2009; n = 1031) and post-SFL (July 2009-2015; n = 890). Compared with those in the pre-SFL group, patients admitted in the post-SFL period had better New York Heart Association (NYHA) functional class (22.1 vs. 38.7 NYHA classes III-IV; P < 0.001) and higher left ventricular ejection fraction (LVEF) (36.1 ± 19.6 vs. 32.6 ± 13.4; P < 0.001). Among STEMI survivors, 101 (6.7%) pre-SFL patients and 40 (2%) post-SFL patients (P < 0.001) fulfilled the criteria for HF clinic referral (Killip-Kimball class ≥ 2 during index admission and/or LVEF of <40%). Furthermore, among patients admitted to the HF clinic, post-STEMI HF with reduced ejection fraction patients comprised 8.9% of the pre-SFL group and only 4.2% of the post-SFL group (P < 0.001)., Conclusions: Among patients treated at our multidisciplinary HF clinic, the adoption of an SFL network has decreased the prevalence of post-STEMI HF with reduced ejection fraction., (© 2017 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of the European Society of Cardiology.)

Objectives: The aim of this study was to analyse baseline characteristics and outcome of patients with heart failure and mid-range left ventricular ejection fraction (HFmrEF, left ventricular ejection fraction (LVEF) 40%-49%) and the effect of 1-year change in LVEF in this group., Setting: Multicentre prospective observational study of ambulatory patients with HF followed up at four university hospitals with dedicated HF units., Participants: Fourteen per cent (n=504) of the 3580 patients included had HFmrEF., Interventions: Baseline characteristics, 1-year LVEF and outcomes were collected. All-cause death, HF hospitalisation and the composite end-point were the primary outcomes., Results: Median follow-up was 3.66 (1.69-6.04) years. All-cause death, HF hospitalisation and the composite end-point were 47%, 35% and 59%, respectively. Outcomes were worse in HF with preserved ejection fraction (HFpEF) (LVEF>50%), without differences between HF with reduced ejection fraction (HFrEF) (LVEF<40%) and HFmrEF (all-cause mortality 52.6% vs 45.8% and 43.8%, respectively, P=0.001). After multivariable Cox regression analyses, no differences in all-cause death and the composite end-point were seen between the three groups. HF hospitalisation and cardiovascular death were not statistically different between patients with HFmrEF and HFrEF. At 1-year follow-up, 62% of patients with HFmrEF had LVEF measured: 24% had LVEF<40%, 43% maintained LVEF 40%-49% and 33% had LVEF>50%. While change in LVEF as continuous variable was not associated with better outcomes, those patients who evolved from HFmrEF to HFpEF did have a better outcome. Those who remained in the HFmrEF and HFrEF groups had higher all-cause mortality after adjustment for age, sex and baseline LVEF (HR 1.96 (95% CI 1.08 to 3.54, P=0.027) and HR 2.01 (95% CI 1.04 to 3.86, P=0.037), respectively)., Conclusions: Patients with HFmrEF have a clinical profile in-between HFpEF and HFrEF, without differences in all-cause mortality and the composite end-point between the three groups. At 1 year, patients with HFmrEF exhibited the greatest variability in LVEF and this change was associated with survival., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: Significant recovery of left ventricular ejection fraction (LVEF) occurs in a proportion of patients with heart failure (HF) and reduced ejection fraction (HFrEF). We analysed outcomes, including mortality [all-cause, cardiovascular (CV), HF-related, and sudden death], and HF-related hospitalizations in this HF-recovered group. The primary endpoint was a composite of CV death or HF hospitalization., Methods and Results: LVEF was assessed at baseline and at 1 year in 1057 consecutive HF patients. Patients were classified into three groups: (i) HF-recovered: LVEF <45% at baseline and ≥45% at 1 year (n = 233); (ii) HF with preserved EF (HFpEF): LVEF ≥45% throughout follow-up (n = 117); and (iii) HFrEF: LVEF <45% throughout follow-up (n = 707). Mean follow-up was 5.6 ± 3.1 years. HF-recovered patients differed from HFrEF and HFpEF groups in demographic and clinical characteristics. The mean LVEF increase was 21.1 ± 10 points in HF-recovered patients. Using the HF-recovered group as a reference, the risks for the primary composite endpoint (n = 376), with non-CV death as competing risk, for HFpEF and HFrEF groups were: hazard ratio (HR) 2.33 [95% confidence interval (CI) 1.60-3.39], P < 0.001 and HR 1.99 (95% CI 1.50-2.65), P < 0.001, respectively. All-cause (n = 429), CV (n = 245), HF-related (n = 127), and sudden death (n = 60) were significantly lower in HF-recovered subjects relative to HFrEF (all P < 0.01). HF-recovered patients also experienced less recurrent HF hospitalizations (P < 0.001)., Conclusion: One in four treated patients with HFrEF showed recovery of systolic function. HF-recovered patients had significantly improved mortality and morbidity relative to HFpEF and HFrEF subjects. Further research is needed to identify optimal medications and device indications for HF-recovered patients., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Aims: To define iron deficiency in chronic heart failure (CHF), both, ferritin<100μg/L (indicating reduced iron storage) and transferrin saturation (TSAT)<20% (indicating reduced iron transport) are used. The aim of the study was to evaluate clinical outcomes and prognosis of either low ferritin or low TSAT in patients with CHF., Methods and Results: We evaluated the clinical impact of impaired iron storage (IIS) and impaired iron transport (IIT) either alone or in combination compared to patients with normal iron status (NIS), in an international cohort of 1821 patients with CHF with a mean age of 66±13years and mean left ventricular ejection fraction of 35%±15. Isolated IIS was observed in 219 patients (12%), isolated IIT in 454 (25%) and coexistence of both conditions (IIS+IIT) were seen in 389 (21%). In adjusted models we found that patients with IIS+IIT and patients with isolated IIT had higher NT-proBNP levels (OR 2.2 [1.6-3.1] and OR 2.1 [1.5-2.9] respectively) and worse quality of life (OR 1.8 [1.2-2.7] and OR 1.7 [1.2-2.5] respectively) compared with isolated IIS. Multivariate Cox analyses showed that IIS+IIT and isolated IIT were independently associated with all-cause mortality (OR 1.41 [1.06-1.86] and OR 1.47 [1.13-1.92] respectively). Patients with isolated IIS did not differ from NIS patients in terms of severity or outcomes., Conclusions: Impaired iron transport alone or in combination with impaired iron storage is associated with worse clinical profile and increased risk of mortality in patients with CHF. Patients with isolated impaired iron storage may have a milder form of iron deficiency., (Copyright © 2017. Published by Elsevier B.V.)

Introduction and Objectives: Heart failure (HF) is associated with a high rate of readmissions within 30 days postdischarge. Strategies to lower readmission rates generally show modest results. To reduce readmission rates, we developed a STructured multidisciplinary outpatient clinic for Old and frail Postdischarge patients hospitalized for HF (STOP-HF-Clinic)., Methods: This prospective all-comers study enrolled patients discharged from internal medicine or geriatric wards after HF hospitalization. The intervention involved a face-to-face early visit (within 7 days), HF nurse education, treatment titration, and intravenous medication when needed. Thirty-day readmission risk was calculated using the CORE-HF risk score. We also studied the impact of 30-day readmission burden on regional health care by comparing the readmission rate in the STOP-HF-Clinic Referral Area (∼250000 people) with that of the rest of the Catalan Health Service (CatSalut) (∼7.5 million people) during the pre-STOP-HF-Clinic (2012-2013) and post-STOP-HF-Clinic (2014-2015) time periods., Results: From February 2014 to June 2016, 518 consecutive patients were included (age, 82 years; Barthel score, 70; Charlson index, 5.6, CORE-HF 30-day readmission risk, 26.5%). The observed all-cause 30-day readmission rate was 13.9% (47.5% relative risk reduction) and the observed HF-related 30-day readmission rate was 7.5%. The CatSalut registry included 65131 index HF admissions, with 9267 all-cause and 6686 HF-related 30-day readmissions. The 30-day readmission rate was significantly reduced in the STOP-HF-Clinic Referral Area in 2014-2015 compared with 2012-2013 (P < .001), mainly driven by fewer HF-related readmissions., Conclusions: The STOP-HF-Clinic, an approach that could be promptly implemented elsewhere, is a valuable intervention for reducing the global burden of early readmissions among elder and vulnerable patients with HF., (Copyright © 2017 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: Heart failure (HF) is frequent and its prevalence is increasing. We aimed to evaluate the epidemiologic features of HF patients, the 1-year follow-up outcomes and the independent predictors of those outcomes at a population level., Methods and Results: Population-based longitudinal study including all prevalent HF cases in Catalonia (Spain) on December 31st, 2012. Patients were divided in 3 groups: patients without a previous HF hospitalization, patients with a remote (>1 year) HF hospitalization and patients with a recent (<1 year) HF admission. We analyzed 1year all-cause and HF hospitalizations, and all-cause mortality. Logistic regression was used to identify the independent predictors of each of those outcomes. A total of 88,195 patients were included. Mean age was 77 years, 55% were women. Comorbidities were frequent. Fourteen percent of patients had never been hospitalized, 71% had a remote HF hospitalization and 15% a recent hospitalization. At 1-year follow-up, all-cause and HF hospitalization were 53% and 8.8%, respectively. One-year all-cause mortality rate was 14%, and was higher in patients with a recent HF hospitalization (24%). The presence of diabetes mellitus, atrial fibrillation or chronic kidney disease was independently associated with all-cause and HF hospitalization and all-cause mortality. Hospital admissions and emergency department visits the previous year were also found to be independently associated with the three study outcomes., Conclusions: Outcomes are different depending on the HF population studied. Some comorbidity, an all-cause hospitalization or emergency department visit the previous year were associated with a worse outcome.

Background: Patients with diabetes mellitus (DM) have an increased risk of developing heart failure (HF). Further, DM is associated with poor prognosis in patients with HF. Our aim was to determine whether DM has any impact on the predictive value of a multi-biomarker panel in patients with HF., Methods: We included 1069 consecutive ambulatory HF patients in the study: age 66.2 ± 12.8 years, 33.5 ± 13.3 left ventricular ejection fraction, 36% diabetic patients. We measured serum concentrations of N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hs-TnT), ST2, galectin-3, high-sensitivity C reactive protein (hs-CRP), cystatin-C, soluble transferrin receptor (sTfR), and neprilysin and followed patients for 4.9 ± 2.8 years. Primary endpoints were all-cause and cardiovascular death., Results: During follow-up, 534 patients died; 283 died of cardiovascular causes. Diabetic subjects had higher mortality (57.7 vs. 45.6%, p < 0.001). NTproBNP (p = 0.07), hs-TnT (p < 0.001), galectin-3 (p < 0.001), and cystatin-C (p = 0.001) concentrations were higher in diabetic patients, whereas sTfR levels were lower (p = 0.005). There were no interactions between DM and NTproBNP, hs-TnT, galectin-3, hs-CRP, cystatin-C, sTfR, and neprilysin relative to risk prediction for all-cause or cardiovascular death. By contrast, ST2 significantly interacted with DM for all-cause (p = 0.02) and cardiovascular (p = 0.03) death. In diabetic patients, HRs for ST2 were 1.27 (95% CI 1.16-1.40, p < 0.001) and 1.23 (95% CI 1.09-1.39, p = 0.001) for all-cause and cardiovascular death, respectively. In nondiabetic patients, HRs for ST2 were 1.53 (95% CI 1.35-1.73, p < 0.001) and 1.64 (95% CI 1.31-2.05, p < 0.001) for all-cause and cardiovascular death, respectively. The multivariable Cox regression analysis showed that hs-TnT and ST2 were the only markers that were independently associated with both all-cause and cardiovascular mortality in patients with HF and diabetes. Moreover, in these patients, the combination of these two markers significantly increased discrimination as assessed by the area under the curve., Conclusions: Biomarkers used in the general population to predict the clinical course of heart failure are also useful in patients with diabetes. In these patients, among all the biomarkers analysed only hs-TnT and ST2 were independently associated with both all-cause and cardiovascular mortality.

Aims: Heart failure (HF) is one of the diseases with greater healthcare expenditure. However, little is known about the cost of HF at a population level. Hence, our aim was to study the population-level distribution and predictors of healthcare expenditure in patients with HF., Methods and Results: This was a population-based longitudinal study including all prevalent HF cases in Catalonia (Spain) on 31 December 2012 (n = 88 195). We evaluated 1-year healthcare resource use and expenditure using the Health Department (CatSalut) surveillance system that collects detailed information on healthcare usage for the entire population. Mean age was 77.4 (12) years; 55% were women. One-year mortality rate was 14%. All-cause emergency department visits and unplanned hospitalizations were required at least once in 53.4% and 30.8% of patients, respectively. During 2013, a total of €536.2 million were spent in the care of HF patients (7.1% of the total healthcare budget). The main source of expenditure was hospitalization (39% of the total) whereas outpatient care represented 20% of the total expenditure. In the general population, outpatient care and hospitalization were the main expenses. In multivariate analysis, younger age, higher presence of co-morbidities, and a recent HF or all-cause hospitalization were independently associated with higher healthcare expenditure., Conclusions: In Catalonia, a large portion of the annual healthcare budget is devoted to HF patients. Unplanned hospitalization represents the main source of healthcare-related expenditure. The knowledge of how expenditure is distributed in a non-selected HF population might allow health providers to plan the distribution of resources in patients with HF., (© 2016 The Authors. European Journal of Heart Failure © 2016 European Society of Cardiology.)

Background: Obese patients with chronic Heart Failure (HF) have better outcome than their lean counterparts, although little is known about the pathophysiology of this obesity paradox. Our aim was to evaluate the hypothesis that patients with chronic HF and obesity (defined as body mass index (BMI)≥30kg/m(2)), may have an attenuated neurohormonal activation in comparison with non-obese patients., Methods and Results: The present study is the post-hoc analysis of a cohort of 742 chronic HF patients from a single-center study evaluating sympathetic activation by measuring baseline levels of norepinephrine (NE). Obesity was present in 33% of patients. Higher BMI and obesity were significantly associated with lower NE levels in multivariable linear regression models adjusted for covariates (p<0.001). Addition to NE in multivariate Cox proportional hazard models attenuated the prognostic impact of BMI in terms of outcomes. Finally, when we explored the prognosis impact of raised NE levels (>70th percentile) carrying out a separate analysis in obese and non-obese patients we found that in both groups NE remained a significant independent predictor of poorer outcomes, despite the lower NE levels in patients with chronic HF and obesity: all-cause mortality hazard ratio=2.37 (95% confidence interval, 1.14-4.94) and hazard ratio=1.59 (95% confidence interval, 1.05-2.4) in obese and non-obese respectively; and cardiovascular mortality hazard ratio=3.08 (95% confidence interval, 1.05-9.01) in obese patients and hazard ratio=2.08 (95% confidence interval, 1.42-3.05) in non-obese patients., Conclusion: Patients with chronic HF and obesity have significantly lower sympathetic activation. This finding may partially explain the obesity paradox described in chronic HF patients., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Santiago Jiménez-Marrero,1,2 Miguel Cainzos-Achirica,1– 4 David Monterde,5 Luis Garcia-Eroles,5 Cristina Enjuanes,1,2 Sergi Yun,1,2,6 Alberto Garay,1,2 Pedro Moliner,1,2 Lidia Alcoberro,1,2 Xavier Corbella,2,6,7 Josep Comin-Colet1,2,8 1Community Heart Failure Program, Department of Cardiology, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 2Bellvitge Biomedical Research Institute (IDIBELL), L’Hospitalet de Llobregat, Barcelona, Spain; 3Johns Hopkins Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins Medical Institutions, Baltimore, MD, USA; 4School of Medicine and Health Sciences, International University of Catalonia, Barcelona, Spain; 5Healthcare Information and Knowledge Unit, Catalan Health Service, Barcelona, Spain; 6Department of Internal Medicine, Bellvitge University Hospital, L’Hospitalet de Llobregat, Barcelona, Spain; 7Hestia Chair in Integrated Health and Social Care, Faculty of Medicine and Health Sciences, Universitat Internacional de Catalunya, Barcelona, Spain; 8Department of Clinical Sciences, School of Medicine, University of Barcelona, Barcelona, SpainCorrespondence: Josep Comin-ColetHospital Universitari de Bellvitge, Department of Cardiology, 19th Floor, Feixa Llarga s/n, 08907 Hospitalet de Llobregat, Barcelona, SpainTel +34932607078Email jcomin@bellvitgehospital.catBackground: 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.Keywords: chronic heart failure, chronic kidney disease, heart failure, hyperkalemia, hypertension, potassium