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Heart failure (HF) is a long‐term clinical syndrome, with increasing prevalence and considerable healthcare costs that are further expected to increase dramatically. Despite significant advances in therapy and prevention, mortality and morbidity remain high and quality of life poor. Epidemiological data, that is, prevalence, incidence, mortality, and morbidity, show geographical variations across the European countries, depending on differences in aetiology, clinical characteristics, and treatment. However, data on the prevalence of the disease are scarce, as are those on quality of life. For these reasons, the ESC‐HFA has developed a position paper to comprehensively assess our understanding of the burden of HF in Europe, in order to guide future policies for this syndrome. This manuscript will discuss the available epidemiological data on HF prevalence, outcomes, and human costs—in terms of quality of life—in European countries. [ABSTRACT FROM AUTHOR]

Genetic cardiomyopathies are disorders of the cardiac muscle, most often explained by pathogenic mutations in genes encoding sarcomere, cytoskeleton, or ion channel proteins. Clinical phenotypes such as heart failure and arrhythmia are classically treated with generic drugs, but aetiology-specific and targeted treatments are lacking. As a result, cardiomyopathies still present a major burden to society, and affect many young and older patients. The Translational Committee of the Heart Failure Association (HFA) and the Working Group of Myocardial Function of the European Society of Cardiology (ESC) organized a workshop to discuss recent advances in molecular and physiological studies of various forms of cardiomyopathies. The study of cardiomyopathies has intensified after several new study setups became available, such as induced pluripotent stem cells, three-dimensional printing of cells, use of scaffolds and engineered heart tissue, with convincing human validation studies. Furthermore, our knowledge on the consequences of mutated proteins has deepened, with relevance for cellular homeostasis, protein quality control and toxicity, often specific to particular cardiomyopathies, with precise effects explaining the aberrations. This has opened up new avenues to treat cardiomyopathies, using contemporary techniques from the molecular toolbox, such as gene editing and repair using CRISPR-Cas9 techniques, antisense therapies, novel designer drugs, and RNA therapies. In this article, we discuss the connection between biology and diverse clinical presentation, as well as promising new medications and therapeutic avenues, which may be instrumental to come to precision medicine of genetic cardiomyopathies. [ABSTRACT FROM AUTHOR]

Aims: Liquid chromatography‐mass spectrometry (LC‐MS/MS) is an objective new technique to assess non‐adherence to medications. We used this method to study the prevalence, predictors and outcomes of non‐adherence in patients with heart failure with reduced left ventricular ejection fraction (HFrEF). Methods and results: This study included 1296 patients with HFrEF from BIOSTAT‐CHF, a study that aimed to optimise guideline‐recommended therapies. Angiotensin‐converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, β‐blockers and loop diuretics were measured in a single spot urine sample at 9 months using LC‐MS/MS. The relationship between medication non‐adherence and the composite endpoint of all‐cause death or heart failure hospitalisation, over a median follow‐up of 21 months, was evaluated. Non‐adherence to at least one prescribed medication was observed in 45.9% of patients. The strongest predictor of non‐adherence was non‐adherence to any of the other medication classes (P < 0.0005). Regional differences within Europe were observed. On multivariable analyses, non‐adherence to ACEi/ARBs and β‐blockers was associated with an increased risk of the composite endpoint [hazard ratio (HR) 1.38, 95% confidence interval (CI) 1.09–1.95, P = 0.008 and HR 1.48, 95% CI 1.12–1.96, P = 0.006, respectively). Non‐adherence to β‐blockers was also associated with an increased risk of death (HR 2.48, 95% CI 1.67–3.68, P < 0.0005). Patients who were non‐adherent to loop diuretics were healthier and had a decreased risk of the composite endpoint (HR 0.69, 95% CI 0.51–0.93, P = 0.014). Non‐adherence to mineralocorticoid receptor antagonists was not related to any clinical outcome. Conclusion: Non‐adherence to medications, assessed by a single urine test, is common and predicts clinical outcomes in patients with HFrEF. [ABSTRACT FROM AUTHOR]

Heart failure (HF) is the major contributor to cardiovascular morbidity and mortality. Given its rising prevalence, the costs of HF care can be expected to increase. Multidisciplinary management of HF can improve quality of care and survival. However, specialized HF programmes are not widely available in most European countries. These circumstances underlie the suggestion of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) for the development of quality of care centres (QCCs). These are defined as health care institutions that provide multidisciplinary HF management at all levels of care (primary, secondary and tertiary), are accredited by the HFA/ESC and are implemented into existing health care systems. Their major goals are to unify and improve the quality of HF care, and to promote collaboration in education and research activities. Three types of QCC are suggested: community QCCs (primary care facilities able to provide non-invasive assessment and optimal therapy); specialized QCCs (district hospitals with intensive care units, able to provide cardiac catheterization and device implantation services), and advanced QCCs (national reference centres able to deliver advanced and innovative HF care and research). QCC accreditation will require compliance with general and specific HFA/ESC accreditation standards. General requirements include confirmation of the centre's existence, commitment to QCC implementation, and collaboration with other QCCs. Specific requirements include validation of the centre's level of care, service portfolio, facilities and equipment, management, human resources, process measures, quality indicators and outcome measures. Audit and recertification at 4-6-year intervals are also required. The implementation of QCCs will evolve gradually, following a pilot phase in selected countries. The present document summarizes the definition, major goals, development, classification and crucial aspects of the accreditation process of the HFA/ESC QCC Programme. [ABSTRACT FROM AUTHOR]

Type 2 diabetes mellitus (T2DM) is common in patients with heart failure (HF) and associated with considerable morbidity and mortality. Significant advances have recently occurred in the treatment of T2DM, with evidence of several new glucose-lowering medications showing either neutral or beneficial cardiovascular effects. However, some of these agents have safety characteristics with strong practical implications in HF [i.e. dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1 RA), and sodium-glucose co-transporter type 2 (SGLT-2) inhibitors]. Regarding safety of DPP-4 inhibitors, saxagliptin is not recommended in HF because of a greater risk of HF hospitalisation. There is no compelling evidence of excess HF risk with the other DPP-4 inhibitors. GLP-1 RAs have an overall neutral effect on HF outcomes. However, a signal of harm suggested in two small trials of liraglutide in patients with reduced ejection fraction indicates that their role remains to be defined in established HF. SGLT-2 inhibitors (empagliflozin, canagliflozin and dapagliflozin) have shown a consistent reduction in the risk of HF hospitalisation regardless of baseline cardiovascular risk or history of HF. Accordingly, SGLT-2 inhibitors could be recommended to prevent HF hospitalisation in patients with T2DM and established cardiovascular disease or with multiple risk factors. The recently completed trial with dapagliflozin has shown a significant reduction in cardiovascular mortality and HF events in patients with HF and reduced ejection fraction, with or without T2DM. Several ongoing trials will assess whether the results observed with dapagliflozin could be extended to other SGLT-2 inhibitors in the treatment of HF, with either preserved or reduced ejection fraction, regardless of the presence of T2DM. This position paper aims to summarise relevant clinical trial evidence concerning the role and safety of new glucose-lowering therapies in patients with HF. [ABSTRACT FROM AUTHOR]

Acute heart failure is one of the main diagnostic and therapeutic challenges in clinical practice due to a non-specific clinical manifestation and the urgent need for timely and tailored management at the same time. In this position statement, the Heart Failure Association aims to systematize the use of various imaging methods in accordance with the timeline of acute heart failure care proposed in the recent guidelines of the European Society of Cardiology. During the first hours of admission the point-of-care focused cardiac and lung ultrasound examination is an invaluable tool for rapid differential diagnosis of acute dyspnoea, which is highly feasible and relatively easy to learn. Several portable and stationary imaging modalities are being increasingly used for the evaluation of cardiac structure and function, haemodynamic and volume status, precipitating myocardial ischaemia or valvular abnormalities, and systemic and pulmonary congestion. This paper emphasizes the central role of the full echocardiographic examination in the identification of heart failure aetiology, severity of cardiac dysfunction, indications for specific heart failure therapy, and risk stratification. Correct evaluation of cardiac filling pressures and accurate prognostication may help to prevent unscheduled short-term readmission. Alternative advanced imaging modalities should be considered to assist patient management in the pre- and post-discharge phase, including cardiac magnetic resonance, computed tomography, nuclear studies, and coronary angiography. The Heart Failure Association addresses this paper to the wide spectrum of acute care and heart failure specialists, highlighting the value of all available imaging techniques at specific stages and in common clinical scenarios of acute heart failure. [ABSTRACT FROM AUTHOR]

The vast majority of acute heart failure episodes are characterized by increasing symptoms and signs of congestion with volume overload. The goal of therapy in those patients is the relief of congestion through achieving a state of euvolaemia, mainly through the use of diuretic therapy. The appropriate use of diuretics however remains challenging, especially when worsening renal function, diuretic resistance and electrolyte disturbances occur. This position paper focuses on the use of diuretics in heart failure with congestion. The manuscript addresses frequently encountered challenges, such as (i) evaluation of congestion and clinical euvolaemia, (ii) assessment of diuretic response/resistance in the treatment of acute heart failure, (iii) an approach towards stepped pharmacologic diuretic strategies, based upon diuretic response, and (iv) management of common electrolyte disturbances. Recommendations are made in line with available guidelines, evidence and expert opinion. [ABSTRACT FROM AUTHOR]

Exercise training (ET) and secondary prevention measures in cardiovascular disease aim to stimulate early physical activity and to facilitate recovery and improve health behaviours. ET has also been proposed for heart failure patients with a ventricular assist device (VAD), to help recovery in the patient's functional capacity. However, the existing evidence in support of ET in these patients remains limited. After a review of current knowledge on the causes of the persistence of limitation in exercise capacity in VAD recipients, and concerning the benefit of ET in VAD patients, the Heart Failure Association of the European Society of Cardiology has developed the present document to provide practical advice on implementing ET. This includes appropriate screening to avoid complications and then starting with early mobilisation, ET prescription is individualised to meet the patient's needs. Finally, gaps in our knowledge are discussed. [ABSTRACT FROM AUTHOR]

This article updates the Heart Failure Association of the European Society of Cardiology (ESC) 2007 classification of advanced heart failure and describes new diagnostic and treatment options for these patients. Recognizing the patient with advanced heart failure is critical to facilitate timely referral to advanced heart failure centres. Unplanned visits for heart failure decompensation, malignant arrhythmias, co-morbidities, and the 2016 ESC guidelines criteria for the diagnosis of heart failure with preserved ejection fraction are included in this updated definition. Standard treatment is, by definition, insufficient in these patients. Inotropic therapy may be used as a bridge strategy, but it is only a palliative measure when used on its own, because of the lack of outcomes data. Major progress has occurred with short-term mechanical circulatory support devices for immediate management of cardiogenic shock and long-term mechanical circulatory support for either a bridge to transplantation or as destination therapy. Heart transplantation remains the treatment of choice for patients without contraindications. Some patients will not be candidates for advanced heart failure therapies. For these patients, who are often elderly with multiple co-morbidities, management of advanced heart failure to reduce symptoms and improve quality of life should be emphasized. Robust evidence from prospective studies is lacking for most therapies for advanced heart failure. There is an urgent need to develop evidence-based treatment algorithms to prolong life when possible and in accordance with patient preferences, increase life quality, and reduce the burden of hospitalization in this vulnerable patient population. [ABSTRACT FROM AUTHOR]

This paper provides a practical clinical application of guideline recommendations relating to the inpatient monitoring of patients with acute heart failure, through the evaluation of various clinical, biomarker, imaging, invasive and non-invasive approaches. Comprehensive inpatient monitoring is crucial to the optimal management of acute heart failure patients. The European Society of Cardiology heart failure guidelines provide recommendations for the inpatient monitoring of acute heart failure, but the level of evidence underpinning most recommendations is limited. Many tools are available for the in-hospital monitoring of patients with acute heart failure, and each plays a role at various points throughout the patient's treatment course, including the emergency department, intensive care or coronary care unit, and the general ward. Clinical judgment is the preeminent factor guiding application of inpatient monitoring tools, as the various techniques have different patient population targets. When applied appropriately, these techniques enable decision making. However, there is limited evidence demonstrating that implementation of these tools improves patient outcome. Research priorities are identified to address these gaps in evidence. Future research initiatives should aim to identify the optimal in-hospital monitoring strategies that decrease morbidity and prolong survival in patients with acute heart failure. [ABSTRACT FROM AUTHOR]

Background: Cardiac resynchronisation therapy (CRT) reduces morbidity and mortality in appropriately selected patients with heart failure and is strongly recommended for such patients by guidelines. A European Society of Cardiology (ESC) CRT survey conducted in 2008-2009 showed considerable variation in guideline adherence and large individual, national and regional differences in patient selection, implantation practice and follow-up. Accordingly, two ESC associations, the European Heart Rhythm Association and the Heart Failure Association, designed a second prospective survey to describe contemporary clinical practice regarding CRT.Methods and Results: A survey of the clinical practice of CRT-P and CRT-D implantation was conducted from October 2015 to December 2016 in 42 ESC member countries. Implanting centres provided information about their hospital and CRT service and were asked to complete a web-based case report form collecting information on patient characteristics, investigations, implantation procedures and complications during the index hospitalisation. The 11 088 patients enrolled represented 11% of the total number of expected implantations in participating countries during the survey period; 32% of patients were aged ≥75 years, 28% of procedures were upgrades from a permanent pacemaker or implantable cardioverter-defibrillator and 30% were CRT-P rather than CRT-D. Most patients (88%) had a QRS duration ≥130 ms, 73% had left bundle branch block and 26% were in atrial fibrillation at the time of implantation. Large geographical variations in clinical practice were observed.Conclusion: CRT Survey II provides a valuable source of information on contemporary clinical practice with respect to CRT implantation in a large sample of ESC member states. The survey permits assessment of guideline adherence and demonstrates variations in patient selection, management, implantation procedure and follow-up strategy. [ABSTRACT FROM AUTHOR]

Aims To determine the prevalence of mitral regurgitation (MR) in a large cohort of consecutive patients undergoing clinically indicated echocardiography and to examine the distribution of primary and secondary MR. Methods and results All patients undergoing an echocardiographic study in 19 European centres within a 3-month period were prospectively included. MR assessment was performed as recommended by the European Association of Cardiovascular Imaging (EACVI). MR was classified according to mechanism as primary or secondary and aetiologies were reported. A total of 63 463 consecutive echocardiographic studies were reviewed. Any degree of MR was described in 15 501 patients. Concomitant valve disease of at least moderate grade was present in 28.5% of patients, being tricuspid regurgitation the most prevalent. In the subgroup of moderate and severe MR (n = 3309), 55% of patients had primary MR and 30% secondary MR. Both mechanisms were described in 14% of the studies. According to Carpentier's classification, 26.7% of MR were classified as I, 19.9% of MR as II, 22.4% of MR as IIIa, and 31.1% of MR as IIIb. Conclusion To date, this is the largest echocardiography-based study to analyse the prevalence and aetiology distribution of MR in Europe. The burden of secondary MR was higher than previously described, representing 30% of patients with significant MR. In our environment, degenerative disease is the most common aetiology of primary MR (60%), whereas ischaemic is the most common aetiology of secondary MR (51%). Up to 70% of patients with severe primary MR may have a Class I indication for surgery. However, the optimal therapeutic approach for secondary MR remains uncertain. [ABSTRACT FROM AUTHOR]

Objectives: Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings and associated clinical outcomes of coronary angiography performed in patients with worsening HF.Methods: The BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) programme enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalised or in the outpatient setting. All patients were included in the present analysis.Results: Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were more often observed as inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger and had better renal function (all p≤0.01). Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalisation (adjusted HR=0.71, 95% CI 0.57 to 0.89, p=0.003) and death (adjusted HR=0.59, 95% CI 0.43 to 0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95% CI 1.10 to 2.64, p=0.016).Conclusions: Coronary angiography was performed in <13% of patients with symptoms and/or signs of worsening HF. These patients were remarkably different from those who did not undergo coronary angiography and had a lower risk of subsequent events. The presence of coronary stenosis on coronary angiography was associated with a worse prognosis. [ABSTRACT FROM AUTHOR]

Aims: The objectives of the present study were to describe epidemiology and outcomes in ambulatory heart failure (HF) patients stratified by left ventricular ejection fraction (LVEF) and to identify predictors for mortality at 1 year in each group.Methods and Results: The European Society of Cardiology Heart Failure Long-Term Registry is a prospective, observational study collecting epidemiological information and 1-year follow-up data in 9134 HF patients. Patients were classified according to baseline LVEF into HF with reduced EF [EF <40% (HFrEF)], mid-range EF [EF 40-50% (HFmrEF)] and preserved EF [EF >50% (HFpEF)]. In comparison with HFpEF subjects, patients with HFrEF were younger (64 years vs. 69 years), more commonly male (78% vs. 52%), more likely to have an ischaemic aetiology (49% vs. 24%) and left bundle branch block (24% vs. 9%), but less likely to have hypertension (56% vs. 67%) or atrial fibrillation (18% vs. 32%). The HFmrEF group resembled the HFrEF group in some features, including age, gender and ischaemic aetiology, but had less left ventricular and atrial dilation. Mortality at 1 year differed significantly between HFrEF and HFpEF (8.8% vs. 6.3%); HFmrEF patients experienced intermediate rates (7.6%). Age, New York Heart Association (NYHA) class III/IV status and chronic kidney disease predicted mortality in all LVEF groups. Low systolic blood pressure and high heart rate were predictors for mortality in HFrEF and HFmrEF. A lower body mass index was independently associated with mortality in HFrEF and HFpEF patients. Atrial fibrillation predicted mortality in HFpEF patients.Conclusions: Heart failure patients stratified according to different categories of LVEF represent diverse phenotypes of demography, clinical presentation, aetiology and outcomes at 1 year. Differences in predictors for mortality might improve risk stratification and management goals. [ABSTRACT FROM AUTHOR]

Despite improvements in medical therapy and device-based treatment, heart failure (HF) continues to impose enormous burdens on patients and health care systems worldwide. Alterations in autonomic nervous system (ANS) activity contribute to cardiac disease progression, and the recent development of invasive techniques and electrical stimulation devices has opened new avenues for specific targeting of the sympathetic and parasympathetic branches of the ANS. The Heart Failure Association of the European Society of Cardiology recently organized an expert workshop which brought together clinicians, trialists and basic scientists to discuss the ANS as a therapeutic target in HF. The questions addressed were: (i) What are the abnormalities of ANS in HF patients? (ii) What methods are available to measure autonomic dysfunction? (iii) What therapeutic interventions are available to target the ANS in patients with HF, and what are their specific strengths and weaknesses? (iv) What have we learned from previous ANS trials? (v) How should we proceed in the future? [ABSTRACT FROM AUTHOR]

Aims Mineralocorticoid receptor antagonists (MRAs) are recommended (unless contraindicated) to all patients with heart failure with reduced ejection fraction (HFrEF). However, MRAs are still largely underused in routine clinical practice. This study aims to describe the determinants and pattern of use of MRAs in HFrEF. Methods and results BIOSTAT-CHF is a European multicentre, prospective study which enrolled patients suboptimally treated with angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEi/ARBs) and/or beta-blockers, with the aim of optimizing guideline-based use of these agents. From the original 2516 subjects, this retrospective post hoc analysis included the 1325 patients with an indication for MRA therapy (i.e. left ventricular ejection fraction ≤35%, estimated glomerular filtration rate ≥30 mL/min/1.73m², K+ ≤5.0 mmol/L). The mean age was 66.1±12.2 years. At baseline an MRA was prescribed to 741 (56%) patients. Patients who were prescribed MRAs at baseline were younger, more often male, had higher body mass index, lower sodium, higher proportion of hypertension history and ACEi/ARB prescription (all P < 0.05). Of the 1049 patients who completed the baseline plus the 9 month visit, 585 (56%) had an MRA prescribed at baseline and 662 (63%) had an MRA prescribed at 9 months. Among the 585 patients with MRA at baseline, 91 (16%) had discontinued therapy and among the 461 (44%) patients without MRA at baseline 168 (36%) had initiated therapy subsequently. MRA discontinuation was more likely in subjects with higher left ventricular ejection fraction and NYHA class III/IV (P < 0.05 for both). MRA prescription both at baseline and 9 months was not associated with the outcome of death or heart failure hospitalization (adjusted hazard ratio 1.02, 95% confidence interval 0.66-1.58; P =0.93). Conclusions In this prospective observational study across Europe, MRAs were largely under-prescribed and frequently discontinued Owing to these dynamic changes, outcome inferences are inconclusive. [ABSTRACT FROM AUTHOR]

Aims: To identify differences in clinical epidemiology, in-hospital management and 1-year outcomes among patients hospitalized for acute heart failure (AHF) and enrolled in the European Society of Cardiology Heart Failure Long-Term (ESC-HF-LT) Registry, stratified by clinical profile at admission. Methods and results: The ESC-HF-LT Registry is a prospective, observational study collecting hospitalization and 1-year follow-up data from 6629 AHF patients. Among AHF patients enrolled in the registry, 13.2% presented with pulmonary oedema (PO), 2.9% with cardiogenic shock (CS), 61.1% with decompensated heart failure (DHF), 4.8% with hypertensive heart failure (HT-HF), 3.5% with right heart failure (RHF) and 14.4% with AHF and associated acute coronary syndromes (ACS-HF). The 1-year mortality rate was 28.1% in PO, 54.0% in CS, 27.2% in DHF, 12.8% in HT-HF, 34.0% in RHF and 20.6% in ACS-HF patients. When patients were classified by systolic blood pressure (SBP) at initial presentation, 1-year mortality was 34.8% in patients with SBP <85 mmHg, 29.0% in those with SBP 85-110 mmHg, 21.2% in patients with SBP 110-140 mmHg and 17.4% in those with SBP >140 mmHg. These differences tended to diminish in the months post-discharge, and 1-year mortality for the patients who survived at least 6 months post-discharge did not vary significantly by either clinical profile or SBP classification. Conclusion Rates of adverse outcomes in AHF remain high, and substantial differences have been found when patients were stratified by clinical profile or SBP. However, patients who survived at least 6 months post-discharge represent a more homogeneous group and their 1-year outcome is less influenced by clinical profile or SBP at admission. [ABSTRACT FROM AUTHOR]

Organ injury and impairment are commonly observed in patients with acute heart failure (AHF), and congestion is an essential pathophysiological mechanism of impaired organ function. Congestion is the predominant clinical profile in most patients with AHF; a smaller proportion presents with peripheral hypoperfusion or cardiogenic shock. Hypoperfusion further deteriorates organ function. The injury and dysfunction of target organs (i.e. heart, lungs, kidneys, liver, intestine, brain) in the setting of AHF are associated with increased risk for mortality. Improvement in organ function after decongestive therapies has been associated with a lower risk for post-discharge mortality. Thus, the prevention and correction of organ dysfunction represent a therapeutic target of interest in AHF and should be evaluated in clinical trials. Treatment strategies that specifically prevent, reduce or reverse organ dysfunction remain to be identified and evaluated to determine if such interventions impact mortality, morbidity and patient-centred outcomes. This paper reflects current understanding among experts of the presentation and management of organ impairment in AHF and suggests priorities for future research to advance the field. [ABSTRACT FROM AUTHOR]

Patients admitted for acute heart failure (AHF) experience high rates of in-hospital and post-discharge morbidity and mortality despite current therapies. Serelaxin is recombinant human relaxin-2, a hormone with vasodilatory and end-organ protective effects believed to play a central role in the cardiovascular and renal adaptations of human pregnancy. In the phase 3 RELAX-AHF trial, serelaxin met its primary endpoint of improving dyspnoea through day 5 in patients admitted for AHF. Compared to placebo, serelaxin also reduced worsening heart failure (WHF) by 47% through day 5 and both all-cause and cardiovascular mortality by 37% through day 180. RELAX-AHF-2 ( ClinicalTrials.gov NCT01870778) is designed to confirm serelaxin's effect on these clinical outcomes. RELAX-AHF-2 is a multicentre, randomized, double-blind, placebo-controlled, event-driven, phase 3 trial enrolling ∼6800 patients hospitalized for AHF with dyspnoea, congestion on chest radiograph, increased natriuretic peptide levels, mild-to-moderate renal insufficiency, and systolic blood pressure ≥125 mmHg. Patients are randomized within 16 h of presentation to 48 h intravenous infusions of serelaxin (30 µg/kg/day) or placebo, both in addition to standard of care treatments. The primary objectives are to demonstrate that serelaxin is superior to placebo in reducing: (i) 180 day cardiovascular death, and (ii) occurrence of WHF through day 5. Key secondary endpoints include 180 day all-cause mortality, composite of 180 day combined cardiovascular mortality or heart failure/renal failure rehospitalization, and in-hospital length of stay during index AHF. The results from RELAX-AHF-2 will provide data on the potential beneficial effect of serelaxin on cardiovascular mortality and WHF in selected patients with AHF. [ABSTRACT FROM AUTHOR]

Aims The aim of this study was to evaluate the in-hospital and 1-year prognostic impact of diabetes and elevated blood glucose levels at hospital admission in patients with acute heart failure (HF). Methods and results We studied a multinational cohort of 6926 hospitalized patients with acute HF enrolled in the European Society of Cardiology (ESC) and Heart Failure Association (HFA) Long-Term Registry, of whom 49.4% (n = 3422) had known or previously undiagnosed diabetes (defined as self-reported history, or medication use, or fasting glucose levels ≥7.0 mmol/L or haemoglobin A1c ≥6.5%). Compared with those without diabetes, patients with known or previously undiagnosed diabetes had higher cumulative rates of in-hospital mortality, 1-year mortality, and 1-year HF re-hospitalization that occurred independently of multiple clinical risk factors: in-hospital mortality [6.8 vs. 4.4%; adjusted hazard ratio (HR) 1.774; 95% confidence interval (CI) 1.282-2.456, P < 0.001], 1-year all-cause mortality (27.5 vs. 24%; adjusted HR 1.162; 95% CI 1.020-1.325, P = 0.024), and 1-year hospital re-admissions for HF (23.2 vs. 18.5%; adjusted HR 1.320; 95% CI 1.139-1.530, P < 0.001). Moreover, elevated admission blood glucose concentrations were powerfully prognostic for in-hospital mortality, but not for 1-year mortality or re-hospitalizations, in both patients with and without diabetes. Conclusions Among patients hospitalized for acute HF, the presence of diabetes is independently associated with an increased risk of in-hospital mortality, 1-year all-cause mortality, and 1-year re-hospitalizations for HF, underscoring the need for more effective and personalized treatments of diabetes in this particularly high-risk patient population. [ABSTRACT FROM AUTHOR]

The aim of this study was to assess the net clinical and prognostic effects of intravenous (i.v.) iron therapy in patients with systolic heart failure (HF) and iron deficiency (ID). We performed an aggregate data meta-analysis (random effects model) of randomized controlled trials that evaluated the effects of i.v. iron therapy in iron-deficient patients with systolic HF. We searched electronic databases up to September 2014. We identified five trials which fulfilled the inclusion criteria (509 patients received i.v. iron therapy in comparison with 342 controls). Intravenous iron therapy has been shown to reduce the risk of the combined endpoint of all-cause death or cardiovascular hospitalization [odds ratio (OR) 0.44, 95% confidence interval (CI) 0.30-0.64, P < 0.0001], and the combined endpoint of cardiovascular death or hospitalization for worsening HF (OR 0.39, 95% CI 0.24-0.63, P = 0.0001). Intravenous iron therapy resulted in a reduction in NYHA class (data are reported as a mean net effect with 95% CIs for all continuous variables) (-0.54 class, 95% CI -0.87 to -0.21, P = 0.001); an increase in 6-min walking test distance (+31 m, 95% CI 18-43, P < 0.0001); and an improvement in quality of life [Kansas City Cardiomyopathy Questionnaire (KCCQ) score +5.5 points, 95% CI 2.8-8.3, P < 0.0001; European Quality of Life-5 Dimensions (EQ-5D) score +4.1 points, 95% CI 0.8-7.3, P = 0.01; Minnesota Living With Heart Failure Questionnaire (MLHFQ) score -19 points, 95% CI:-23 to -16, P < 0.0001; and Patient Global Assessment (PGA) +0.70 points, 95% CI 0.31-1.09, P = 0004]. The evidence indicates that i.v. iron therapy in iron-deficient patients with systolic HF improves outcomes, exercise capacity, and quality of life, and alleviates HF symptoms. [ABSTRACT FROM AUTHOR]

Recent advances in care and management of heart failure have improved outcome, largely as a result of the developing evidence basis for medications, implantable devices and the organization of heart failure follow-up. Such developments have also increased the complexity of delivering and coordinating care. This has led to a change to the way in which heart failure services are organized and to the traditional role of the heart failure nurse. Nurses in many countries now provide a range of services that include providing care for patients with acute and with chronic heart failure, working in and across different sectors of care (inpatient, outpatient, community care, the home and remotely), organising care services around the face-to-face and the remote collection of patient data, and liaising with a wide variety of health-care providers and professionals. To support such advances the nurse requires a skill set that goes beyond that of their initial education and training. The range of nurses' roles across Europe is varied. So too is the nature of their educational preparation. This heart failure nurse curriculum aims to provide a framework for use in countries of the European Society of Cardiology. Its modular approach enables the key knowledge, skills, and behaviours for the nurse working in different care settings to be outlined and so facilitate nursing staff to play a fuller role within the heart failure team. [ABSTRACT FROM AUTHOR]

Aims: The 'obesity paradox' is consistently observed in patients with heart failure (HF). We investigated the relationship of body surface area (BSA) to mortality and hospitalizations in patients with chronic HF.Methods and Results: Data from the outpatient cohort of the observational, prospective, Heart Failure Long-Term Registry of the Heart Failure Association of the European Society of Cardiology was analysed in order to evaluate the prognostic significance of BSA in chronic HF. A total of 9104 chronic HF patients (age 64.8 ± 13.4 years; 71.6% males) were enrolled. Mortality during 1-year follow-up was observed in 718 of 8875 (8.1%) patients. A progressive, inverse relationship between all-cause mortality and BSA levels was observed; the adjusted hazard ratio (HR) for 1-year mortality was 1.823 [95% confidence interval (CI) 1.398-2.376], P < 0.001 for the lowest quartile of BSA <1.78 m(2) , and 1.255, 95% CI 1.000-1.576, P = 0.05 for the middle two quartiles (1.78 ≤BSA ≤2.07 m(2) ), compared with the highest quartile (BSA >2.07 m(2) ). For each increase of 0.1 m(2) in BSA, an adjusted HR of 0.908 (95% CI 0.870-0.948), P < 0.001 for mortality was calculated. HF hospitalizations were not associated with BSA subgroup distribution. In both genders, subjects within the lowest BSA quartile (males <1.84 m(2) and females <1.64 m(2) ) had significantly higher mortality rates during follow-up (log-rank P < 0.0001). However, the stepwise association with mortality was more distinct in males.Conclusions: Total and cardiovascular mortality, but not HF hospitalizations was inversely associated with BSA levels in chronic HF patients. BSA may serve as a prognostic indicator for adverse outcome in HF patients. [ABSTRACT FROM AUTHOR]

Aims: Despite major improvements in pharmacological and device treatments, heart failure remains a syndrome with high morbidity and mortality, poor quality of life, and high health-care costs. Given the extensive heterogeneity among patients with heart failure, substantial differences in the response to therapy can be expected. We hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure.Methods: The BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF) included 2516 patients with worsening signs and/or symptoms of heart failure from 11 European countries, who were considered to be on suboptimal medical treatment. Another 1738 patients from Scotland were included in a validation cohort. Overall, both patient cohorts were well matched. The majority of patients were hospitalized for acute heart failure, and the remainder presented with worsening signs and/or symptoms of heart failure at outpatient clinics. Approximately half of the patients were in New York Heart Association class III, and 7% vs 34% of patients of the index vs validation cohort had heart failure with preserved ejection fraction. According to study design, all patients used diuretics, but owing to the inclusion criteria of both cohorts, patients were not on optimal, evidence-based medical therapy. In the follow-up phase, uptitration to guideline-recommended doses was encouraged.Conclusion: By using a novel systems biology approach, incorporating demographics, biomarkers, genome-wide analysis, and proteomics, a model that predicts response to therapy will be developed, which should be instrumental in developing alternative therapies for patients with suboptimal response to currently recommended therapies and thus further improve care for patients with heart failure. [ABSTRACT FROM AUTHOR]

Aims: The European Society of Cardiology Heart Failure Long-Term Registry (ESC-HF-LT-R) was set up with the aim of describing the clinical epidemiology and the 1-year outcomes of patients with heart failure (HF) with the added intention of comparing differences between participating countries.Methods and Results: The ESC-HF-LT-R is a prospective, observational registry contributed to by 211 cardiology centres in 21 European and/or Mediterranean countries, all being member countries of the ESC. Between May 2011 and April 2013 it collected data on 12 440 patients, 40.5% of them hospitalized with acute HF (AHF) and 59.5% outpatients with chronic HF (CHF). The all-cause 1-year mortality rate was 23.6% for AHF and 6.4% for CHF. The combined endpoint of mortality or HF hospitalization within 1 year had a rate of 36% for AHF and 14.5% for CHF. All-cause mortality rates in the different regions ranged from 21.6% to 36.5% in patients with AHF, and from 6.9% to 15.6% in those with CHF. These differences in mortality between regions are thought reflect differences in the characteristics and/or management of these patients.Conclusion: The ESC-HF-LT-R shows that 1-year all-cause mortality of patients with AHF is still high while the mortality of CHF is lower. This registry provides the opportunity to evaluate the management and outcomes of patients with HF and identify areas for improvement. [ABSTRACT FROM AUTHOR]

Aims: To assess physicians' adherence to guideline-recommended medications for the treatment of chronic heart failure (CHF) with reduced ejection fraction.Methods and Results: QUALIFY is an international prospective observational longitudinal survey of 7092 CHF outpatients recruited 1-15 months after hospitalization for heart failure from September 2013 to December 2014 in 547 centres in 36 countries. We constructed a five-class guideline adherence score for angiotensin converting enzyme inhibitors (ACEIs), beta-blockers, angiotensin receptor blockers (ARBs), mineralocorticoid receptor antagonists, and ivabradine. The adherence score was good in 67%, moderate in 25%, and poor in 8% of patients. Adherence was lower in women than men but there were differences in age (65.7 ± 12.5 years women vs. 62.2 ± 12.4 years men, P < 0.001) and the proportion of women at ≥50% target dose of beta-blockers was lower in those >67 years (median) (11% vs. 16.2%, P = 0.005). Geographic variations were observed with lower adherence scores in Central/Eastern European countries. The proportion of patients at target dose and ≥50% of target dose was low (27.9% and 63.3% for ACEIs, 14.8% and 51.8% for beta-blockers, 6.9% and 39.5% for ARBs, and 6.9% and 39.5% for ivabradine, respectively). It was also lower in patients most recently hospitalized (<6  vs. ≥6 months) except for beta-blockers.Conclusion: This international survey shows that adherence to guideline-recommended medications is relatively satisfactory but the dosage of recommended CHF medications is usually suboptimal. Action plans aimed at improving adherence to guidelines are required. [ABSTRACT FROM AUTHOR]

Takotsubo syndrome is an acute reversible heart failure syndrome that is increasingly recognized in modern cardiology practice. This Position Statement from the European Society of Cardiology Heart Failure Association provides a comprehensive review of the various clinical and pathophysiological facets of Takotsubo syndrome, including nomenclature, definition, and diagnosis, primary and secondary clinical subtypes, anatomical variants, triggers, epidemiology, pathophysiology, clinical presentation, complications, prognosis, clinical investigations, and treatment approaches. Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision-making by practising clinicians. These also cover more complex areas (e.g. uncertain diagnosis and delayed presentation) and the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation. The unmet needs and future directions for research in this syndrome are also discussed. [ABSTRACT FROM AUTHOR]

Aim& Methods: One critical factor enhancing the implementation of successful diagnostic and therapeutic strategies into clinical practice is awareness among the lay public. We describe awareness in a contemporary, multinational convenience sample of subjects attending the Heart Failure Awareness (HFA) Day Initiatives in 2013.Results: We analysed 2,438 subjects (Germany 33%, Lithuania 42%, Romania 8%, Slovenia 17%) : 53% were female, 58% were aged >60 years, 11% (had) worked in the medical sector, 82% heard about HF before. Shortness of breath and tiredness were correctly identified as symptoms of heart failure in 71% and 61%, but only 52% recognized swelling of feet and legs as a clinical sign; 31% considered heart failure a normal symptom of old age, and only 38% realized the particularly poor prognosis after a heart failure related hospitalization. Subjects who had heard about heart failure before had a lower prevalence of common misbeliefs about HF.Conclusion: In subjects participating in the HFA Day initiative 2013, the level of awareness was unsatisfactory, and important misconceptions remain. The educational and awareness activities for both the population at large and also for decision makers should be broadened and intensified. [ABSTRACT FROM AUTHOR]

Aims In heart failure ( HF), exercise training programmes ( ETPs) are a well-recognized intervention to improve symptoms, but are still poorly implemented. The Heart Failure Association promoted a survey to investigate whether and how cardiac centres in Europe are using ETPs in their HF patients. Methods and results The co-ordinators of the HF working groups of the countries affiliated to the European Society of Cardiology ( ESC) distributed and promoted the 12-item web-based questionnaire in the key cardiac centres of their countries. Forty-one country co-ordinators out of the 46 contacted replied to our questionnaire (89%). This accounted for 170 cardiac centres, responsible for 77 214 HF patients. The majority of the participating centres (82%) were general cardiology units and the rest were specialized rehabilitation units or local health centres. Sixty-seven (40%) centres [responsible for 36 385 (48%) patients] did not implement an ETP. This was mainly attributed to the lack of resources (25%), largely due to lack of staff or lack of financial provision. The lack of a national or local pathway for such a programme was the reason in 13% of the cases, and in 12% the perceived lack of evidence on safety or benefit was cited. When implemented, an ETP was proposed to all HF patients in only 55% of the centres, with restriction according to severity or aetiology. Conclusions With respect to previous surveys, there is evidence of increased availability of ETPs in HF in Europe, although too many patients are still denied a highly recommended therapy, mainly due to lack of resources or logistics. [ABSTRACT FROM AUTHOR]

The European Society of Cardiology heart failure guidelines firmly recommend regular physical activity and structured exercise training (ET), but this recommendation is still poorly implemented in daily clinical practice outside specialized centres and in the real world of heart failure clinics. In reality, exercise intolerance can be successfully tackled by applying ET. We need to encourage the mindset that breathlessness may be evidence of signalling between the periphery and central haemodynamic performance and regular physical activity may ultimately bring about favourable changes in myocardial function, symptoms, functional capacity, and increased hospitalization-free life span and probably survival. In this position paper, we provide practical advice for the application of exercise in heart failure and how to overcome traditional barriers, based on the current scientific and clinical knowledge supporting the beneficial effect of this intervention. [ABSTRACT FROM PUBLISHER]

Aims The primary objective of the new ESC-HF Pilot Survey was to describe the clinical epidemiology of outpatients and inpatients with heart failure (HF) and the diagnostic/therapeutic processes applied across 12 participating European countries. This pilot study was specifically aimed at validating the structure, performance, and quality of the data set, for continuing the survey into a permanent registry. Methods and results The ESC-HF Pilot study is a prospective, multicentre, observational survey conducted in 136 cardiology centres from 12 European countries selected to represent the different health systems and care attitudes across Europe. All outpatients with HF and patients admitted for acute HF were included during the enrolment period (1 day per week for 8 consecutive months). From October 2009 to May 2010, 5118 patients were included in this pilot survey, of which 1892 (37%) were admitted for acute HF and 3226 (63%) for chronic HF. Ischaemic aetiology was reported in about half of the patients. In patients admitted for acute HF, the most frequent clinical profile was decompensated HF (75% of cases), whereas pulmonary oedema and cardiogenic shock were reported, respectively, in 13.3 and 2.3% of the cases. The total in-hospital mortality rate was 3.8% and was cardiovascular in 90.1% of the cases. Lowest and highest mortality rates were observed in hypertensive HF and in cardiogenic shock, respectively. More than 80% of patients with chronic HF were treated with renin–angiotensin–aldosterone system blockers and β-adrenergic blockers. However, target doses of such drugs were reached in one-third to one-fourth of the patients only. Conclusion The ESC-HF Pilot Survey is an example of the possibility of utilizing an observational methodology to get insights into the current clinical practice in Europe, whose picture will be completed by the 1-year follow-up. Moreover, this study offered the opportunity to refine the organizational structure of a long-term, extended European network. [ABSTRACT FROM AUTHOR]

Introduction: From a prospective multicentre multicountry clinical trial, we developed and validated risk models to predict prospective all-cause mortality and hospitalizations because of heart failure (HF) in patients with HF.Methods and Results: BIOSTAT-CHF is a research programme designed to develop and externally validate risk models to predict all-cause mortality and HF hospitalizations. The index cohort consisted of 2516 patients with HF from 69 centres in 11 European countries. The external validation cohort consisted of 1738 comparable patients from six centres in Scotland, UK. Patients from the index cohort had a mean age of 69 years, 27% were female, 83% were in New York Heart Association (NYHA) class II-III and the mean left ventricular ejection fraction (LVEF) was 31%. The full prediction models for mortality, hospitalization owing to HF, and the combined outcome, yielded c-statistic values of 0.73, 0.69, and 0.71, respectively. Predictors of mortality and hospitalization owing to HF were remarkably different. The five strongest predictors of mortality were more advanced age, higher blood urea nitrogen and N-terminal pro-B-type natriuretic peptide, lower haemoglobin, and failure to prescribe a beta-blocker. The five strongest predictors of hospitalization owing to HF were more advanced age, previous hospitalization owing to HF, presence of oedema, lower systolic blood pressure and lower estimated glomerular filtration rate. Patients from the validation cohort were aged 74 years, 34% were female, 85% were in NYHA class II-III, and mean LVEF was 41%; c-statistic values for the full and compact model were comparable to the index cohort.Conclusion: A small number of variables, which are usually readily available in the routine clinical setting, provide useful prognostic information for patients with HF. Predictors of mortality were remarkably different from predictors of hospitalization owing to HF. [ABSTRACT FROM AUTHOR]

The article offers information on the Heart Failure Congress 2014 to be held by the Heart Failure Association of the European Society of Cardiology in Athens, Greece.

The article provides a summary of practical recommendations for the prehospital and early management of patients with acute heart failure syndromes. These recommendations were developed from a meeting of experts in cardiology, emergency medicine, and intensive care medicine from Europe and the U.S. These are based on a clinical classification system considering the initial systolic blood pressure and other symptoms.

Cardio-oncology is a rapidly growing field of cardiovascular (CV) medicine that has resulted from the continuously increasing clinical demand for specialized CV evaluation, prevention and management of patients suffering or surviving from malignant diseases. Dealing with CV disease in patients with cancer requires special knowledge beyond that included in the general core curriculum for cardiology. Therefore, the European Society of Cardiology (ESC) has developed a special core curriculum for cardio-oncology, a consensus document that defines the level of experience and knowledge required for cardiologists in this particular field. It is structured into 8 chapters, including (i) principles of cancer biology and therapy; (ii) forms and definitions of cancer therapy-related cardiovascular toxicity (CTR-CVT); (iii) risk stratification, prevention and monitoring protocols for CTR-CVT; (iv) diagnosis and management of CV disease in patients with cancer; (v) long-term survivorship programmes and cardio-oncology rehabilitation; (vi) multidisciplinary team management of special populations; (vii) organization of cardio-oncology services; (viii) research in cardio-oncology. The core curriculum aims at promoting standardization and harmonization of training and evaluation in cardio-oncology, while it further provides the ground for an ESC certification programme designed to recognize the competencies of certified specialists., (© 2023 European Society of Cardiology.)

Aims: Heart failure outcomes remain poor despite advances in therapy. The European Society of Cardiology Heart Failure III Registry (ESC HF III Registry) aims to characterize HF clinical features and outcomes and to assess implementation of guideline-recommended therapy in Europe and other ESC affiliated countries., Methods: Between 1 November 2018 and 31 December 2020, 10 162 patients with chronic or acute/worsening HF with reduced, mildly reduced, or preserved ejection fraction were enrolled from 220 centres in 41 European or ESC affiliated countries. The ESC HF III Registry collected data on baseline characteristics (hospital or clinic presentation), hospital course, diagnostic and therapeutic decisions in hospital and at the clinic visit; and on outcomes at 12-month follow-up. These data include demographics, medical history, physical examination, biomarkers and imaging, quality of life, treatments, and interventions - including drug doses and reasons for non-use, and cause-specific outcomes., Conclusion: The ESC HF III Registry will provide comprehensive and unique insight into contemporary HF characteristics, treatment implementation, and outcomes, and may impact implementation strategies, clinical discovery, trial design, and public policy., (© 2023 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aims: Elderly patients with heart failure with reduced ejection fraction (HFrEF) have worse prognosis and less often receive guideline-recommended therapies. We aim to better understand the underlying pathophysiological processes associated with ageing in HFrEF potentially leading to targeted therapies in this vulnerable population., Methods and Results: From a panel of 363 cardiovascular biomarkers available in 1611 patients with HFrEF in the BIOSTAT-CHF index cohort and cross-validated in 823 patients in the BIOSTAT-CHF validation cohort, we tested which biomarkers were dysregulated in patients aged >75 vs. <65 years. Second, pathway overrepresentation analyses were performed to identify biological pathways linked to higher plasma concentrations of biomarkers in elderly vs. younger patients. After adjustment, multiple test correction [false discovery rate (FDR) 1%], and cross-validation, 27/363 biomarkers were associated with older age, 22 positively and 5 negatively. The biomarkers that were positively associated with older age were associated with tumour cell regulation, extra-cellular matrix organization, and inflammatory processes, whereas biomarkers negatively associated with older age were associated with pathways that may point to cell proliferation and tumourigenesis. Among the 27 biomarkers, WFDC2 (WAP four-disulphide core domain protein 2)-that broadly functions as a protease inhibitor-was associated with older age and had the strongest association with all outcomes. No protein-by-sex interaction was observed., Conclusions: In elderly HFrEF patients, pathways associated with extra-cellular matrix organization, inflammatory processes, and tumour cell regulation were activated, while pathways associated with tumour proliferation functions were down-regulated. These findings may help in a better understanding of the ageing processes in HFrEF and identify potential therapeutic targets., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Background We recently showed that, in patients with heart failure, lower high-density lipoprotein (HDL) cholesterol concentration was a strong predictor of death or hospitalization for heart failure. In a follow-up study, we suggested that this association could be partly explained by HDL proteome composition. However, whether the emerging concept of HDL function contributes to the prognosis of patients with heart failure has not been addressed. Methods and Results We measured 3 key protective HDL function metrics, namely, cholesterol efflux, antioxidative capacity, and anti-inflammatory capacity, at baseline and after 9 months in 446 randomly selected patients with heart failure from BIOSTAT-CHF (A Systems Biology Study to Tailored Treatment in Chronic Heart Failure). Additionally, the relationship between HDL functionality and HDL proteome composition was determined in 86 patients with heart failure. From baseline to 9 months, HDL cholesterol concentrations were unchanged, but HDL cholesterol efflux and anti-inflammatory capacity declined (both P <0.001). In contrast, antioxidative capacity increased ( P <0.001). Higher HDL cholesterol efflux was associated with lower mortality after adjusting for BIOSTAT-CHF risk models and log HDL cholesterol (hazard ratio, 0.81; 95% CI, 0.71-0.92; P =0.001). Other functionality measures were not associated with outcome. Several HDL proteins correlated with HDL functionality, mainly with cholesterol efflux. Apolipoprotein A1 emerged as the main protein associated with all 3 HDL functionality measures. Conclusions Better HDL cholesterol efflux at baseline was associated with lower mortality during follow-up, independent of HDL cholesterol. HDL cholesterol efflux and anti-inflammatory capacity declined during follow-up in patients with heart failure. Measures of HDL function may provide clinical information in addition to HDL cholesterol concentration in patients with heart failure.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and Academic Research Consortium (ARC), comprised of leading heart failure (HF) academic research investigators, patients, United States (US) Food and Drug Administration representatives, and industry members from the US and Europe. A series of meetings were convened to establish definitions and key concepts for the evaluation of HF therapies including optimal medical and device background therapy, clinical trial design elements and statistical concepts, and study endpoints. This manuscript summarizes the expert panel discussions as consensus recommendations focused on populations and endpoint definitions; it is not exhaustive or restrictive, but designed to stimulate HF clinical trial innovation., (© Copyright 2020 European Society of Cardiology and American College of Cardiology.)

Background: Geographical differences may impact the treatment of heart failure (HF) and the results of clinical trials. We have investigated the differences between geographical areas across Europe in the BIOSTAT-CHF program., Methods: Patients with worsening HF enrolled in BIOSTAT-CHF were subdivided, according to the European geographical areas, into those from Northern countries (The Netherlands, Norway, Sweden, UK), Central countries (Germany, Poland, Serbia, Slovenia), and Mediterranean countries (France, Greece, Italy). Patients were compared for baseline characteristics, treatment, and outcomes. The primary endpoint was a composite of all-cause mortality or HF hospitalization., Results: Among 2516 patients enrolled in BIOSTAT-CHF, 814 (32.3%) were from Northern European centers, 816 (32.4%) from Central European centers, and 886 (35.2%) from Mediterranean centers. Patients from Northern European centers were older, had more severe signs and symptoms of HF, and with lower incidence of non-cardiac comorbidities such as chronic kidney dysfunction, diabetes and, hypertension, compared to those from the Central and Mediterranean centers. Patients receiving ≥ 50% of the target dose of both ACE-I/ARB after the up-titration phase were higher in the Northern European centers compared with the other regions (60% versus 58.7% in the Central European centers and 46.5% in the Mediterranean ones; p < 0.001). The primary endpoint occurred at a higher rate in the Northern centers (44.3% versus 37.4% in central centers and 39.6% in Mediterranean centers; p = 0.014), this difference became non-significant after the adjustment for important confounders. Importantly, treatment up-titration reduced the event rates regardless of the geographical region (p for interaction > 0.05)., Conclusion: The BIOSTAT-CHF study showed significant differences in the clinical features, treatment and prognosis in European patients with HF. Patients from the Mediterranean centers less often had the HF treatments up-titrated; however, the treatment up-titration benefited patients irrespective of their geographical region and should be part of the "default" clinical practice.

The coronavirus disease 2019 (COVID-19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has important implications for the safety of participants in clinical trials and the research staff caring for them and, consequently, for the trials themselves. Patients with heart failure may be at greater risk of infection with COVID-19 and the consequences might also be more serious, but they are also at risk of adverse outcomes if their clinical care is compromised. As physicians and clinical trialists, it is our responsibility to ensure safe and effective care is delivered to trial participants without affecting the integrity of the trial. The social contract with our patients demands no less. Many regulatory authorities from different world regions have issued guidance statements regarding the conduct of clinical trials during this COVID-19 crisis. However, international trials may benefit from expert guidance from a global panel of experts to supplement local advice and regulations, thereby enhancing the safety of participants and the integrity of the trial. Accordingly, the Heart Failure Association of the European Society of Cardiology on 21 and 22 March 2020 conducted web-based meetings with expert clinical trialists in Europe, North America, South America, Australia, and Asia. The main objectives of this Expert Position Paper are to highlight the challenges that this pandemic poses for the conduct of clinical trials in heart failure and to offer advice on how they might be overcome, with some practical examples. While this panel of experts are focused on heart failure clinical trials, these discussions and recommendations may apply to clinical trials in other therapeutic areas., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

Aims: The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors., Methods and Results: We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations., Conclusion: In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: journals.permissions@oup.com.)

The European Society of Cardiology (ESC) has published a series of guidelines on heart failure (HF) over the last 25 years, most recently in 2016. Given the amount of new information that has become available since then, the Heart Failure Association (HFA) of the ESC recognized the need to review and summarise recent developments in a consensus document. Here we report from the HFA workshop that was held in January 2019 in Frankfurt, Germany. This expert consensus report is neither a guideline update nor a position statement, but rather a summary and consensus view in the form of consensus recommendations. The report describes how these guidance statements are supported by evidence, it makes some practical comments, and it highlights new research areas and how progress might change the clinical management of HF. We have avoided re-interpretation of information already considered in the 2016 ESC/HFA guidelines. Specific new recommendations have been made based on the evidence from major trials published since 2016, including sodium-glucose co-transporter 2 inhibitors in type 2 diabetes mellitus, MitraClip for functional mitral regurgitation, atrial fibrillation ablation in HF, tafamidis in cardiac transthyretin amyloidosis, rivaroxaban in HF, implantable cardioverter-defibrillators in non-ischaemic HF, and telemedicine for HF. In addition, new trial evidence from smaller trials and updated meta-analyses have given us the chance to provide refined recommendations in selected other areas. Further, new trial evidence is due in many of these areas and others over the next 2 years, in time for the planned 2021 ESC guidelines on the diagnosis and treatment of acute and chronic heart failure., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Aims: Association of elevated circulating levels of trimethylamine N-oxide (TMAO) with adverse outcomes in patients with heart failure (HF) has been described. However, response of TMAO levels to treatment and medications has not been investigated. Therefore, we investigated whether TMAO levels are responsive to guideline-recommended treatment and medications, and further reflect changes in outcomes., Methods and Results: TMAO levels were investigated in the systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure (BIOSTAT-CHF), which addressed response to guideline-recommended pharmacological treatment. TMAO levels in 2234 patients with new-onset or progressively worsening HF showed strong associations with adverse events (mortality and/or rehospitalisation) at 1, 2 and 3 years [hazard ratio (HR) 1.37-1.51, P ≤ 0.019). Analysis of 972 patients with plasma available at both enrolment and follow-up visit showed reductions of B-type natriuretic peptide (BNP) levels with guideline-based treatment (P < 0.001), but not for TMAO levels. Moreover, patients with higher TMAO levels than median before and after treatment showed increased association with adverse outcomes [HR 2.21, 95% confidence interval (CI) 1.43-3.43, P < 0.001] compared to patients with lower than median levels either before or after treatment (HR 1.13, 95% CI 0.63-2.04, P = 0.684 and HR 1.14, 95% CI 0.64-2.03, P = 0.662, respectively)., Conclusion: TMAO levels were associated with adverse outcomes (mortality and/or rehospitalisation) in BIOSTAT-CHF, and did not respond to guideline-based pharmacological treatment in contrast to BNP levels which did as expected. Lower TMAO levels were associated with favourable outcome regardless of treatment., (© 2018 The Authors. European Journal of Heart Failure © 2018 European Society of Cardiology.)

Natriuretic peptide [NP; B-type NP (BNP), N-terminal proBNP (NT-proBNP), and midregional proANP (MR-proANP)] concentrations are quantitative plasma biomarkers for the presence and severity of haemodynamic cardiac stress and heart failure (HF). End-diastolic wall stress, intracardiac filling pressures, and intracardiac volumes seem to be the dominant triggers. This paper details the most important indications for NPs and highlights 11 key principles underlying their clinical use shown below. NPs should always be used in conjunction with all other clinical information. NPs are reasonable surrogates for intracardiac volumes and filling pressures. NPs should be measured in all patients presenting with symptoms suggestive of HF such as dyspnoea and/or fatigue, as their use facilitates the early diagnosis and risk stratification of HF. NPs have very high diagnostic accuracy in discriminating HF from other causes of dyspnoea: the higher the NP, the higher the likelihood that dyspnoea is caused by HF. Optimal NP cut-off concentrations for the diagnosis of acute HF (very high filling pressures) in patients presenting to the emergency department with acute dyspnoea are higher compared with those used in the diagnosis of chronic HF in patients with dyspnoea on exertion (mild increase in filling pressures at rest). Obese patients have lower NP concentrations, mandating the use of lower cut-off concentrations (about 50% lower). In stable HF patients, but also in patients with other cardiac disorders such as myocardial infarction, valvular heart disease, atrial fibrillation or pulmonary embolism, NP concentrations have high prognostic accuracy for death and HF hospitalization. Screening with NPs for the early detection of relevant cardiac disease including left ventricular systolic dysfunction in patients with cardiovascular risk factors may help to identify patients at increased risk, therefore allowing targeted preventive measures to prevent HF. BNP, NT-proBNP and MR-proANP have comparable diagnostic and prognostic accuracy. In patients with shock, NPs cannot be used to identify cause (e.g. cardiogenic vs. septic shock), but remain prognostic. NPs cannot identify the underlying cause of HF and, therefore, if elevated, must always be used in conjunction with cardiac imaging., (© 2019 The Authors. European Journal of Heart Failure © 2019 European Society of Cardiology.)

Fibrosis is a pivotal player in heart failure development and progression. Measurements of (markers of) fibrosis in tissue and blood may help to diagnose and risk stratify patients with heart failure, and its treatment may be effective in preventing heart failure and its progression. A lack of pathophysiological insights and uniform definitions has hampered the research in fibrosis and heart failure. The Translational Research Committee of the Heart Failure Association discussed several aspects of fibrosis in their workshop. Early insidious perturbations such as subclinical hypertension or inflammation may trigger first fibrotic events, while more dramatic triggers such as myocardial infarction and myocarditis give rise to full blown scar formation and ongoing fibrosis in diseased hearts. Aging itself is also associated with a cardiac phenotype that includes fibrosis. Fibrosis is an extremely heterogeneous phenomenon, as several stages of the fibrotic process exist, each with different fibrosis subtypes and a different composition of various cells and proteins - resulting in a very complex pathophysiology. As a result, detection of fibrosis, e.g. using current cardiac imaging modalities or plasma biomarkers, will detect only specific subforms of fibrosis, but cannot capture all aspects of the complex fibrotic process. Furthermore, several anti-fibrotic therapies are under investigation, but such therapies generally target aspecific aspects of the fibrotic process and suffer from a lack of precision. This review discusses the mechanisms and the caveats and proposes a roadmap for future research., (© 2019 The Authors. European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)