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Abstract Aims Several mechanisms have been identified in the aetiopathogenesis of heart failure with preserved ejection fraction (HFpEF). Among these, coronary microvascular dysfunction (CMD) may play a key pathophysiological role. We performed a systematic review and meta‐analysis to investigate the prevalence, echocardiographic correlates, and prognostic implications of CMD in patients with HFpEF. Methods and results A systematic search for articles up to 1 May 2023 was performed. The primary aim was to assess the prevalence of CMD. Secondary aims were to compare key echocardiographic parameters (E/e′ ratio, left atrial volume index [LAVi], and left ventricular mass index [LVMi]), clinical outcomes [death and hospitalization for heart failure (HF)], and prevalence of atrial fibrillation (AF) between patients with and without CMD. Meta‐regressions according to baseline patient characteristics and study features were performed to explore potential heterogeneity sources. We identified 14 observational studies, enrolling 1138 patients with HFpEF. The overall prevalence of CMD was 58%. Compared with patients without CMD, patients with HFpEF and CMD had larger LAVi [mean difference (MD) 3.85 confidence interval (CI) 1.19–6.5, P

Abstract The notion of a constant relationship between resistance and capacitance (RC time) in the pulmonary circulation has been challenged by more recent research. The RC time can be obtained using either a simplified empirical approach or a semilogarithmic equation. Although direct curve-fit analysis is a feasible and ostensibly reference approach for RC analysis, it remains largely unexplored. We aimed to study the relationship between various RC methods in different states of pulmonary hemodynamics. Methods In total, 182 patients underwent clinically indicated right heart catheterization. The pressure curves were exported and processed using the MATLAB software. We calculated the RC time using the empirical method (RCEST), semilogarithmic approach (RCSL), and direct measurement of curve fit (RCFIT). Results Among 182 patients, 137 had pulmonary hypertension due to left heart disease (PH-LHD), 35 had pulmonary arterial hypertension (PAH), and 10 demonstrated normal hemodynamics (non-PH). RCEST consistently overestimated the RCFIT and RCSL measurements by a mean of 75%. With all three methods, the RC values were longer in the PAH (RCFIT = 0.36 ± 0.14 s) than in the PH-LHD (0.27 ± 0.1 s) and non-PH (0.27 ± 0.09 s) groups (p

Abstract Aims In patients with heart failure (HF), we aimed to assess (i) the time trends in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) testing; (ii) patient characteristics associated with NT‐proBNP testing; (iii) distribution of NT‐proBNP levels, focusing on the subgroups with (WHFE) vs. without (NWHFE) a worsening HF event, defined as an HF hospitalization; and (iv) changes of NT‐proBNP levels over time. Methods and results NT‐proBNP testing and levels were investigated in HF patients enrolled in the Swedish Heart Failure Registry (SwedeHF) linked with the Stockholm CREAtinine Measurements project from January 2011 to December 2018. Index date was the first registration in SwedeHF. Patterns of change in NT‐proBNP levels before (in the previous 6 ± 3 months) and after (in the following 6 ± 3 months) the index date were categorized as follows: (i)

Abstract While excessive production of reactive oxygen species (ROS) is a characteristic hallmark of numerous diseases, clinical approaches that ameliorate oxidative stress have been unsuccessful. Here, utilizing multi-omics, we demonstrate that in cardiomyocytes, mitochondrial isocitrate dehydrogenase (IDH2) constitutes a major antioxidative defense mechanism. Paradoxically reduced expression of IDH2 associated with ventricular eccentric hypertrophy is counterbalanced by an increase in the enzyme activity. We unveil redox-dependent sex dimorphism, and extensive mutual regulation of the antioxidative activities of IDH2 and NRF2 by a feedforward network that involves 2-oxoglutarate and L-2-hydroxyglutarate and mediated in part through unconventional hydroxy-methylation of cytosine residues present in introns. Consequently, conditional targeting of ROS in a murine model of heart failure improves cardiac function in sex- and phenotype-dependent manners. Together, these insights may explain why previous attempts to treat heart failure with antioxidants have been unsuccessful and open new approaches to personalizing and, thereby, improving such treatment.

Abstract Aim Acyl ghrelin increases cardiac output (CO) in heart failure with reduced ejection fraction (HFrEF). This could impair the right ventricular‐pulmonary arterial coupling (RVPAC), both through an increased venous return and right ventricular afterload. We aim to investigate if acyl ghrelin increases CO with or without worsening the right‐sided haemodynamics in HFrEF assessed by RVPAC. Methods and results The Karolinska Acyl ghrelin Trial was a randomized double‐blind placebo‐controlled trial of acyl ghrelin versus placebo (120‐min intravenous infusion) in HFrEF. RVPAC was assessed echocardiographically at baseline and 120 min. ANOVA was used for difference in change between acyl ghrelin versus placebo, adjusted for baseline values. Of the 30 randomized patients, 22 had available RVPAC (acyl ghrelin n = 12, placebo n = 10). Despite a 15% increase in CO in the acyl ghrelin group (from 4.0 (3.5–4.6) to 4.6 (3.9–6.1) L/min, P = 0.003), RVPAC remained unchanged; 5.9 (5.3–7.6) to 6.3 (4.8–7.5) mm·(m/s)−1, P = 0.372, while RVPAC was reduced in the placebo group, 5.2 (4.3–6.4) to 4.8 (4.2–5.8) mm·(m/s)−1, P = 0.035. Comparing change between groups, CO increased in the acyl ghrelin group versus placebo (P = 0.036) while RVPAC and the right ventricular pressure gradient remained unchanged. Conclusion Treatment with acyl ghrelin increases CO while preserving or even improving RVPAC in HFrEF, possibly due to increased contractility, reduced PVR and/or reduced left sided filling pressures. These potential effects strengthen the role of acyl ghrelin therapy in HFrEF with right ventricular failure.

Little is known either about either physical activity patterns, or other lifestyle-related prevention measures in heart transplantation (HTx) recipients. The history of HTx started more than 50 years ago but there are still no guidelines or position papers highlighting the features of prevention and rehabilitation after HTx. The aims of this scientific statement are (i) to explain the importance of prevention and rehabilitation after HTx, and (ii) to promote the factors (modifiable/non-modifiable) that should be addressed after HTx to improve patients’ physical capacity, quality of life and survival. All HTx team members have their role to play in the care of these patients and multidisciplinary prevention and rehabilitation programmes designed for transplant recipients. HTx recipients are clearly not healthy disease-free subjects yet they also significantly differ from heart failure patients or those who are supported with mechanical circulatory support. Therefore, prevention and rehabilitation after HTx both need to be specifically tailored to this patient population and be multidisciplinary in nature. Prevention and rehabilitation programmes should be initiated early after HTx and continued during the entire post-transplant journey. This clinical consensus statement focuses on the importance and the characteristics of prevention and rehabilitation designed for HTx recipients.

AimsTo assess the barriers to guideline-directed medical therapy (GDMT) use in heart failure (HF), diagnostic workup and general knowledge about HF among physicians in Sweden.MethodsA survey about the management of HF was sent to 828 Swedish physicians including general practitioners (GPs) and specialists during 2021–2022. Answers were reported as percentages and comparisons were made by specialty (GPs vs. specialists).ResultsOne hundred sixty-eight physicians participated in the survey (40% females, median age 43 years; 41% GPs and 59% specialists). Electrocardiography and New York Heart Association class evaluations are mostly performed once a year by GPs (46%) and at every outpatient visit by specialists (40%). Echocardiography is mostly requested if there is clinical deterioration (60%). One-third of participants screen for iron deficiency only if there is anemia. Major obstacles to implementation of different drug classes in HF with reduced ejection fraction are related to side effects, with no significant differences between specialties. Device implantation is deemed appropriate regardless of aetiology (69%) and patient age (86%). Specialists answered correctly to knowledge questions more often than GPs. Eighty-six percent of participants think that GDMT should be implemented as much as possible. Most participants (57%) believe that regular patient assessment in nurse-led HF clinics improve adherence to GDMT.ConclusionObstacles to GDMT implementation according to physicians in Sweden mainly relate to potential side effects, lack of specialist knowledge and organizational aspects. Further efforts should be placed in educational activities and structuring of nurse-led clinics.

Abstract Aims In heart failure with preserved ejection fraction (HFpEF), regional heterogeneity of clinical phenotypes is increasingly recognized, with coronary microvascular dysfunction (CMD) potentially being a common shared feature. We sought to determine the regional differences in clinical characteristics and prevalence of CMD in HFpEF. Methods and results We analysed clinical characteristics and CMD in 202 patients with stable HFpEF (left ventricular ejection fraction ≥40%) in Finland, Singapore, Sweden, and United States in the multicentre PROMIS‐HFpEF study. Patients with unrevascularized macrovascular coronary artery disease were excluded. CMD was assessed using Doppler echocardiography and defined as coronary flow reserve (adenosine‐induced vs. resting flow)

Abstract The COVID-19 pandemic has had a significant impact on global public health, with long-term consequences that are still largely unknown. This study aimed to assess the data regarding acute cardiovascular hospital admissions in five European centers before and during the pandemic. A multicenter, multinational observational registry was created, comparing admissions to the emergency departments during a 3-months period in 2020 (during the pandemic) with the corresponding period in 2019 (pre-pandemic). Data on patient demographics, COVID-19 test results, primary diagnosis, comorbidities, heart failure profile, medication use, and laboratory results were collected. A total of 8778 patients were included in the analysis, with 4447 patients in 2019 and 4331 patients in 2020. The results showed significant differences in the distribution of cardiovascular diseases between the two years. The frequency of pulmonary embolism (PE) increased in 2020 compared to 2019, while acute heart failure (AHF) and other cardiovascular diseases decreased. The odds of PE incidence among hospitalized patients in 2020 were 1.316-fold greater than in 2019. The incidence of AHF was 50.83% less likely to be observed in 2020, and the odds for other cardiovascular diseases increased by 17.42% between the 2 years. Regarding acute coronary syndrome (ACS), the distribution of its types differed between 2019 and 2020, with an increase in the odds of ST-segment elevation myocardial infarction (STEMI) in 2020. Stratification based on sex revealed further insights. Among men, the incidence of AHF decreased in 2020, while other cardiovascular diseases increased. In women, only the incidence of STEMI showed a significant increase. When analyzing the influence of SARS-CoV-2 infection, COVID-positive patients had a higher incidence of PE compared to COVID-negative patients. COVID-positive patients with ACS also exhibited symptoms of heart failure more frequently than COVID-negative patients. These findings provide valuable information on the impact of the COVID-19 pandemic on acute cardiovascular hospital admissions. The increased incidence of PE and changes in the distribution of other cardiovascular diseases highlight the importance of monitoring and managing cardiovascular health during and post pandemic period. The differences observed between sexes emphasize the need for further research to understand potential sex-specific effects of COVID-19 on cardiovascular outcomes.

Abstract Although the development of therapies and tools for the improved management of heart failure (HF) continues apace, day‐to‐day management in clinical practice is often far from ideal. A Cardiovascular Round Table workshop was convened by the European Society of Cardiology (ESC) to identify barriers to the optimal implementation of therapies and guidelines and to consider mitigation strategies to improve patient outcomes in the future. Key challenges identified included the complexity of HF itself and its treatment, financial constraints and the perception of HF treatments as costly, failure to meet the needs of patients, suboptimal outpatient management, and the fragmented nature of healthcare systems. It was discussed that ongoing initiatives may help to address some of these barriers, such as changes incorporated into the 2021 ESC HF guideline, ESC Heart Failure Association quality indicators, quality improvement registries (e.g. EuroHeart), new ESC guidelines for patients, and the universal definition of HF. Additional priority action points discussed to promote further improvements included revised definitions of HF ‘phenotypes’ based on trial data, the development of implementation strategies, improved affordability, greater regulator/payer involvement, increased patient education, further development of patient‐reported outcomes, better incorporation of guidelines into primary care systems, and targeted education for primary care practitioners. Finally, it was concluded that overarching changes are needed to improve current HF care models, such as the development of a standardized pathway, with a common adaptable digital backbone, decision‐making support, and data integration, to ensure that the model ‘learns’ as the management of HF continues to evolve.

Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) is associated with cardiovascular (CV) and non‐CV events, but long‐term risk is poorly studied. We assessed incidence and predictors of the long‐term CV and non‐CV events. Methods and results Patients presenting with acute HF, EF ≥ 45%, and N‐terminal pro‐brain natriuretic peptide > 300 ng/L were enrolled in the Karolinska‐Rennes study in 2007–11 and were reassessed after 4–8 weeks in a stable state. Long‐term follow‐up was conducted in 2018. The Fine–Gray sub‐distribution hazard regression was used to detect predictors of CV and non‐CV deaths, investigated separately from baseline acute presentation (demographic data only) and from the 4–8 week outpatient visit (including echocardiographic data). Of 539 patients enrolled [median age 78 (interquartile range: 72–84) years; 52% female], 397 patients were available for the long‐term follow‐up. Over a median follow‐up time from acute presentation of 5.4 (2.1–7.9) years, 269 (68%) patients died, 128 (47%) from CV and 120 (45%) from non‐CV causes. Incidence rates per 1000 patient‐years were 62 [95% confidence interval (CI) 52–74] for CV and 58 (95% CI 48–69) for non‐CV death. Higher age and coronary artery disease (CAD) were independent predictors of CV death, and anaemia, stroke, kidney disease, and lower body mass index (BMI) and sodium concentrations of non‐CV death. From the stable 4–8 week visit, anaemia, CAD, and tricuspid regurgitation (>3.1 m/s) were independent predictors of CV death, and higher age of non‐CV death. Conclusions In patients with acute decompensated HFpEF, over 5 years of follow‐up, nearly two‐thirds of patients died, half from CV and the other half from non‐CV causes. CAD and tricuspid regurgitation were associated with CV death. Stroke, kidney disease, lower BMI, and lower sodium were associated with non‐CV death. Anaemia and higher age were associated with both outcomes. [Correction added on 24 March 2023, after first online publication: In the first sentence of the Conclusions, ‘two‐thirds’ has been inserted before ‘of patients died...’ in this version.]

Heart failure (HF) is a global pandemic affecting 64 million people worldwide. HF with preserved ejection fraction (HFpEF) has traditionally received less attention than its main counterpart, HF with reduced ejection fraction (HFrEF). The incidence and prevalence of HFpEF show geographic variation and are increasing over time, soon expected to surpass those of HFrEF. Morbidity and mortality rates of HFpEF are considerable, albeit lower than those of HFrEF. This review focuses on the burden of HFpEF, providing contemporary data on epidemiology, clinical characteristics and comorbidities, cause-specific outcomes, costs and pharmacotherapy.

Abstract Aims Use of left ventricular assist devices (LVADs) in older patients has increased, and assessing outcomes in older LVAD recipients is important. Therefore, this study aimed to investigate associations between age and outcomes after continuous‐flow LVAD (cf‐LVAD) implantation. Methods and results Cf‐LVAD patients from the multicentre European PCHF‐VAD registry were included and categorized into those

Abstract Aims Data on sex and left ventricular assist device (LVAD) utilization and outcomes have been conflicting and mostly confined to US studies incorporating older devices. This study aimed to investigate sex‐related differences in LVAD utilization and outcomes in a contemporary European LVAD cohort. Methods and results This analysis is part of the multicentre PCHF‐VAD registry studying continuous‐flow LVAD patients. The primary outcome was all‐cause mortality. Secondary outcomes included ventricular arrhythmias, right ventricular failure, bleeding, thromboembolism, and the haemocompatibility score. Multivariable Cox regression models were used to assess associations between sex and outcomes. Overall, 457 men (81%) and 105 women (19%) were analysed. At LVAD implant, women were more often in Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) profile 1 or 2 (55% vs. 41%, P = 0.009) and more often required temporary mechanical circulatory support (39% vs. 23%, P = 0.001). Mean age was comparable (52.1 vs. 53.4 years, P = 0.33), and median follow‐up duration was 344 [range 147–823] days for women and 435 [range 190–816] days for men (P = 0.40). No significant sex‐related differences were found in all‐cause mortality (hazard ratio [HR] 0.79 for female vs. male sex, 95% confidence interval [CI] [0.50–1.27]). Female LVAD patients had a lower risk of ventricular arrhythmias (HR 0.56, 95% CI [0.33–0.95]) but more often experienced right ventricular failure. No significant sex‐related differences were found in other outcomes. Conclusions In this contemporary European cohort of LVAD patients, far fewer women than men underwent LVAD implantation despite similar clinical outcomes. This is important as the proportion of female LVAD patients (19%) was lower than the proportion of females with advanced HF as reported in previous studies, suggesting underutilization. Also, female patients were remarkably more often in INTERMACS profile 1 or 2, suggesting later referral for LVAD therapy. Additional research in female patients is warranted.

Summary: Background: There are calls to integrate serial recordings of health related quality of life (HRQoL) into routine care, clinical trials and prognosis. Little is known about the relationship between change in HRQoL and outcomes in heart failure (HF) patients by age, sex and HF subtype. Method: From the Swedish Heart Failure Registry (SwedeHF; 2008–2019), patients were categorised by reduced (

Abstract Aims ARIADNE aimed to assess the association between effects of sacubitril/valsartan and no sacubitril/valsartan treatment and clinical characteristics, functional capacity, and clinical outcomes (cause‐specific mortality and hospitalizations) in outpatients with heart failure (HF) with reduced ejection fraction (HFrEF). Methods ARIADNE was a prospective European registry of 9069 patients with HFrEF treated by office‐based cardiologists or selected primary care physicians. Of the 8787 eligible for analysis, 4173 patients were on conventional HF treatment (non‐S/V group), whereas 4614 patients were either on sacubitril/valsartan treatment at enrolment or started sacubitril/valsartan within 1 month of enrolment (S/V group). We also generated a restricted analysis set (rS/V) including only those 2108 patients who started sacubitril/valsartan treatment within the month prior to or after enrolment. Results At the baseline, average age of patients enrolled in the study was 68 years, and 23.9% (2099/8787) were female. At the baseline, the proportions of patients with New York Heart Association (NYHA) Class III symptoms were 30.9 (1288/4173), 42.8 (1974/4614), and 48.2% (1015/2108), in non‐S/V, S/V, and rS/V groups, respectively. After 12 months of treatment, the proportion of patients with NYHA Class III at baseline who improved to Class II was 32.0% (290/907) in the non‐S/V group vs. 46.3% (648/1399) in S/V group and 48.7% (349/717) in rS/V group. The overall mortality rate was 5.0 per 100 patient‐years. Rates of HF hospitalizations were high (20.9, 20.3, and 21.2 per 100 patient‐years in the non‐S/V, S/V, and rS/V groups, respectively). Emergency room visits without hospitalization occurred in 3.9, 3.2, and 3.9% of patients in the non‐S/V, S/V, and rS/V groups, respectively. Conclusions This large HFrEF European registry provides a contemporary outcome profile of outpatients with HFrEF treated with or without sacubitril/valsartan. In a real‐world setting, sacubitril/valsartan was associated with an improvement of symptoms in patients with HFrEF compared with the conventional HFrEF treatment.

Abstract 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 Aims No biomarker has achieved widespread acceptance as a surrogate endpoint for early‐phase heart failure (HF) trials. We assessed whether changes over time in a panel of plasma biomarkers were associated with subsequent morbidity/mortality in HF with reduced ejection fraction (HFrEF). Methods and results In 1040 patients with HFrEF from the BIOSTAT‐CHF cohort, we investigated the associations between changes in the plasma concentrations of 30 biomarkers, before (baseline) and after (9 months) attempted optimization of guideline‐recommended therapy, on top of the BIOSTAT risk score and the subsequent risk of HF hospitalization/all‐cause mortality using Cox regression models. C‐statistics were calculated to assess discriminatory power of biomarker changes/month‐nine assessment. Changes in N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) and WAP four‐disulphide core domain protein HE4 (WAP‐4C) were the only independent predictors of the outcome after adjusting for their baseline plasma concentration, 28 other biomarkers (both baseline and changes), and BIOSTAT risk score at baseline. When adjusting for month‐nine rather than baseline biomarkers concentrations, only changes in NT‐proBNP were independently associated with the outcome. The C‐statistic of the model including the BIOSTAT risk score and NT‐proBNP increased by 4% when changes were considered on top of baseline concentrations and by 1% when changes in NT‐proBNP were considered on top of its month‐nine concentrations and the BIOSTAT risk score. Conclusions Among 30 relevant biomarkers, a change over time was significantly and independently associated with HF hospitalization/all‐cause death only for NT‐proBNP. Changes over time were modestly more prognostic than baseline or end‐values alone. Changes in biomarkers should be further explored as potential surrogate endpoints in early phase HF trials.

Abstract Aim We present the baseline characteristics of the PREFERS Stockholm epidemiological study on the natural history and course of new onset heart failure (HF) aiming to improve phenotyping focusing on HF with preserved left ventricular ejection fraction (HFpEF) pathophysiology. Methods and results New onset HF patients diagnosed in hospital or at outpatient HF clinics were included at five Stockholm hospitals 2015–2018 and characterized by N‐terminal pro brain natriuretic peptide (NT‐proBNP), biomarkers, echocardiography, and cardiac magnetic resonance imaging (subset). HFpEF [left ventricular ejection fraction (LVEF) ≥ 50%] was compared with HF with mildly reduced LVEF (HFmrEF; LVEF 41–49%) and with HF with reduced LVEF (HFrEF; LVEF ≤ 40%). We included 547 patients whereof HFpEF (n = 137; 25%), HFmrEF (n = 61; 11%), and HFrEF (n = 349; 64%). HFpEF patients were older (76; 70–81 years; median; interquartile range) than HFrEF (67; 58–74; P 34 mL/m2 in 57% vs. 61% (P = 0.040). HFmrEF patients were intermediary between HFpEF and HFrEF for LV mass, LV volumes, and RV volumes but had the highest proportion of left ventricular hypertrophy and the lowest proportion of elevated E/é. Conclusions Phenotype data in new onset HF patients recruited in a broad clinical setting showed that 25% had HFpEF, were older, more often women, and had greater comorbidity burden. PREFERS is well suited to further explore biomarker and imaging components of HFpEF pathophysiology and may contribute to the emerging knowledge of HF epidemiology. Clinical trial registration: Clinicaltrials.gov identifier: NCT03671122.

Heart failure (HF) is a rapidly growing public health issue with an estimated prevalence of 64 million people globally. Although the incidence of HF has stabilised worldwide and seems to be declining in developed countries, the prevalence is increasing due to the ageing of the population, improved survival after MI and improved treatment and survival of patients with HF. Yet, HF remains associated with high mortality and morbidity, poor quality of life and functional capacity, and confers a substantial burden to the healthcare system. The prevalence, incidence, mortality and morbidity rates reported show geographical variations, depending on the different aetiologies and clinical characteristics observed among patients with HF. In this review, we provide an overview of the global epidemiology of HF with updated data on prevalence, incidence, mortality and morbidity worldwide.

Background: Primary graft failure (PGF) remains the most common cause of short-term mortality after heart transplantation. The main objective was to develop and validate a risk model for prediction of short-term mortality due to PGF after heart transplantation using the ISHLT Heart Transplant Registry. Methods: We developed a non-linear artificial neural networks (ANN) model to evaluate the association between recipient-donor variables and post-transplant PGF. Patients in the ISHLT registry were randomly divided into derivation and an independent internal validation cohort. The primary endpoint was PGF defined as death within 30 days due to Graft failure or Cardiovascular causes or retransplant within 30 days for causes other than rejection. Results: Among 64,964 adult recipients transplanted between 1994 and 2013, mean age was 51 years and 22% were female. The incidence of PGF up to 30 days was 3.7%. The ANN model selected 33 of 77 risk variables as relevant for PGF prediction. The C-index in the test cohort was 0.70 (95% CI: 0.68-0.71). The risk variables which most influenced the PGF were underlying HF diagnosis, ischemia time and sex, while renal function had a lower influence. Conclusion: An ANN model to predict primary graft dysfunction was derived and independently validated. The good discrimination of the ANN model likely results from its flexibility to model potentially non-linear relationships and interactions. Whether this model with improved discrimination can assist in clinical decisions at the time of transplant should be tested.

Abstract Aims Factors influencing follow‐up referral decisions and their prognostic implications are poorly investigated in patients with heart failure (HF) with reduced (HFrEF), mildly reduced (HFmrEF), and preserved (HFpEF) ejection fraction (EF). We assessed (i) the proportion of, (ii) independent predictors of, and (iii) outcomes associated with follow‐up in specialty vs. primary care across the EF spectrum. Methods and results We analysed 75 518 patients from the large and nationwide Swedish HF registry between 2000–2018. Multivariable logistic regression models were fitted to identify the independent predictors of planned follow‐up in specialty vs. primary care, and multivariable Cox models to assess the association between follow‐up type and outcomes. In this nationwide registry, 48 115 (64%) patients were planned for follow‐up in specialty and 27 403 (36%) in primary care. The median age was 76 [interquartile range (IQR) 67–83] years and 27 546 (36.5%) patients were female. Key independent predictors of planned follow‐up in specialty care included optimized HF care, that is follow‐up in a nurse‐led HF clinic [odds ratio (OR) 4.60, 95% confidence interval (95% CI) 4.41–4.79], use of HF devices (OR 3.99, 95% CI 3.62–4.40), beta‐blockers (OR 1.39, 95% CI 1.32–1.47), renin–angiotensin system/angiotensin‐receptor‐neprilysin inhibitors (OR 1.21, 95% CI 1.15–1.27), and mineralocorticoid receptor antagonists (OR 1.31, 95% CI 1.26–1.37); and more severe HF, that is higher NT‐proBNP (OR 1.13, 95% CI 1.06–1.20) and NYHA class (OR 1.13, 95% CI 1.08–1.19). Factors associated with lower likelihood of follow‐up in specialty care included older age (OR 0.29, 95% CI 0.28–0.30), female sex (OR 0.89, 95% CI 0.86–0.93), lower income (OR 0.79, 95% CI 0.76–0.82) and educational level (OR 0.77, 95% CI 0.73–0.81), higher EF [HFmrEF (OR 0.65, 95% CI 0.62–0.68) and HFpEF (OR 0.56, 95% CI 0.53–0.58) vs. HFrEF], and higher comorbidity burden, such as presence of kidney disease (OR 0.91, 95% CI 0.87–0.95), atrial fibrillation (OR 0.85, 95% CI 0.81–0.89), and diabetes mellitus (OR 0.92, 95% CI 0.88–0.96). A planned follow‐up in specialty care was independently associated with lower risk of all‐cause [hazard ratio (HR) 0.78, 95% CI 0.76–0.80] and cardiovascular death (HR 0.76, 95% CI 0.73–0.78) across the EF spectrum, but not of HF hospitalization (HR 1.06, 95% CI 1.03–1.10). Conclusions In a large nationwide HF population, referral to specialty care was linked with male sex, younger age, lower EF, lower comorbidity burden, better socioeconomic environment and optimized HF care, and associated with better survival across the EF spectrum. Our findings highlight the need for greater and more equal access to HF specialty care and improved quality of primary care.

Abstract Aims In the heart failure (HF) with preserved ejection fraction (HFpEF) PARAGON‐HF trial, sacubitril/valsartan vs. valsartan improved mortality/morbidity in patients with left ventricular ejection fraction (LVEF) below median (57%). We assessed eligibility for sacubitril/valsartan based on four scenarios. Methods and results Eligibility was assessed in the Karolinska‐Rennes study (acute HFpEF, LVEF ≥ 45%, and N‐terminal pro‐B‐type natriuretic peptide ≥300 pg/mL subsequently assessed as outpatients including echocardiography) in (i) a trial scenario (all trial criteria); (ii) a pragmatic scenario (selected trial criteria); (iii) LVEF below lower limit of normal range (

Abstract In heart failure (HF), acute decompensation can occur quickly and unexpectedly because of worsening of chronic HF or to new‐onset HF diagnosed for the first time (‘de novo’). Patients presenting with acute HF (AHF) have a poor prognosis comparable with those with acute myocardial infarction, and any delay of treatment initiation is associated with worse outcomes. Recent HF guidelines and recommendations have highlighted the importance of a timely diagnosis and immediate treatment for patients presenting with AHF to decrease disease progression and improve prognosis. However, based on the available data, there is still uncertainty regarding the optimal ‘time‐to‐treatment’ effect in AHF. Furthermore, the immediate post‐worsening HF period plays an important role in clinical outcomes in HF patients after hospitalization and is known as the ‘vulnerable phase’ characterized by high risk of readmission and early death. Early and intensive treatment for HF patients in the ‘vulnerable phase’ might be associated with lower rates of early readmission and mortality. Additionally, in the chronic stable HF outpatient, treatments are often delayed or not initiated when symptoms are stable, ignoring the risk for adverse outcomes such as sudden death. Consequently, there is a dire need to better identify HF patients during hospitalization and after discharge and treating them adequately to improve their prognosis. HF is an urgent clinical scenario along all its stages and disease conditions. Therefore, time plays a significant role throughout the entire patient's journey. Therapy should be optimized as soon as possible, because this is beneficial regardless of severity or duration of HF. Time lavished before treatment initiation is recognized as important modifiable risk factor in HF.

Abstract Aims We assessed the outcome of hospitalized coronavirus disease 2019 (COVID‐19) patients with heart failure (HF) compared with patients with other cardiovascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia). We further wanted to determine the incidence of HF events and its consequences in these patient populations. Methods and results International retrospective Postgraduate Course in Heart Failure registry for patients hospitalized with COVID‐19 and CArdioVascular disease and/or risk factors (arterial hypertension, diabetes, or dyslipidaemia) was performed in 28 centres from 15 countries (PCHF‐COVICAV). The primary endpoint was in‐hospital mortality. Of 1974 patients hospitalized with COVID‐19, 1282 had cardiovascular disease and/or risk factors (median age: 72 [interquartile range: 62–81] years, 58% male), with HF being present in 256 [20%] patients. Overall in‐hospital mortality was 25% (n = 323/1282 deaths). In‐hospital mortality was higher in patients with a history of HF (36%, n = 92) compared with non‐HF patients (23%, n = 231, odds ratio [OR] 1.93 [95% confidence interval: 1.44–2.59], P

Background Heart failure (HF) has a dramatic impact on worldwide health care systems that is determined by the growing prevalence of and the high exposure to cardiovascular and noncardiovascular events. Prognosis remains poor. We sought to compare a large population with HF across the ejection fraction (EF) spectrum with a population without HF for patient characteristics, and HF, cardiovascular, and noncardiovascular outcomes. Methods and Results Patients with HF registered in the Swedish HF registry in 2005 to 2018 were compared 1:3 with a sex‐, age‐, and county‐matched population without HF. Outcomes were cardiovascular and noncardiovascular mortality and hospitalizations. Of 76 453 patients with HF, 53% had reduced EF, 23% mildly reduced EF, and 24% preserved EF. Compared with those without HF, patients with HF had more cardiovascular and noncardiovascular comorbidities and worse socioeconomic status. Incidence of cardiovascular and noncardiovascular events was higher in people with HF versus non‐HF, with increased risk of all‐cause (hazard ratio [HR], 2.53 [95% CI, 2.50–2.56]), cardiovascular (HR, 4.67 [95% CI, 4.59–4.76]), and noncardiovascular (HR, 1.49 [95% CI, 1.46–1.52]) mortality, 2‐ to 5‐fold higher risk of first/repeated cardiovascular and noncardiovascular hospitalizations, and ~4 times longer in‐hospital length of stay for any cause. Patients with HF with reduced EF had higher risk of HF hospitalizations, whereas those with HF with preserved EF had higher risk of all‐cause and noncardiovascular hospitalization and mortality. Conclusions Patients with HF exert a high health care burden, with a much higher risk of cardiovascular, all‐cause, and noncardiovascular events, and nearly 4 times as many days spent in hospital compared with those without HF. These epidemiological data may enable strategies for optimal resource allocation and HF trial design.

Abstract Aims Heart failure (HF) with preserved ejection fraction (HFpEF) has poor long‐term prognosis. We assessed rates and predictors of outcome 10 years after an acute episode of HF. Methods and results The Karolinska‐Rennes (KaRen) study enrolled HFpEF patients with acute HF, ejection fraction ≥ 45%, and N‐terminal pro‐brain natriuretic peptide > 300 ng/L in 2007–11. Clinical data were collected at enrolment and after 4–8 weeks including detailed echocardiography. Follow‐up data were collected 10 years after study initiation, starting from 6 months after enrolment until 2018 assessed by telephone. Independent predictors of primary (all‐cause mortality or HF hospitalization) and secondary (all‐cause mortality) outcomes were assessed by multivariable Cox regression. Of 539 patients, long‐term follow‐up data were available for 397 patients [52% female; median (interquartile range) age 79 (73, 84) years]. Over a follow‐up of 5.44 (2.06–7.89) years, 1, 3, 5, and 10 year mortality rates were 15%, 31%, 47%, and 74%, respectively, with an incidence rate of 130/1000 patient‐years. The primary outcome was met in 84% of the population, with an incidence rate of 227/1000 patient‐years. The independent predictors of the primary outcome were tricuspid regurgitation peak velocity (m/s) [hazard ratio 1.87 (1.34–2.62)], diabetes mellitus [1.75 (1.11–2.74)], and cancer [1.75 (1.01–3.03)] while female sex was associated with reduced risk [0.64 (0.41–0.98)]. Conclusions In HFpEF, 1, 3, 5, and 10 year mortality was 15%, 31%, 47%, and 74% and mortality or first HF hospitalization was 35%, 54%, 67%, and 84%, respectively. Independent predictors of mortality or HF hospitalization were tricuspid regurgitation peak velocity, diabetes mellitus, cancer, and male sex. In clinical management of HFpEF, attention should be paid to both cardiac and non‐cardiac conditions.

Background: Assessment of pulmonary vascular resistance (PVR) is critical for accurate diagnosis and optimal pharmacotherapy in pulmonary hypertension. We aimed to test the diagnostic performance of a novel, Doppler-based method to evaluate PVR based on Ohm’s law (PVRecho) using pragmatic estimates of pulmonary capillary wedge pressure (PCWP). Methods and results: Simultaneous right heart catheterization (RHC) and echocardiography was performed in a derivation cohort of 111 patients in sinus rhythm referred for PH evaluation and PVRecho independently validated in 238 patients. PVRecho was calculated using pulmonary artery mean pressure estimates (PAMPecho) obtained from peak tricuspid gradient employing a fixed right atrial pressure estimate, PCWPecho was estimated as 10 or 20 mmHg using age-related mitral E/A cut-offs and cardiac output from left ventricular outflow. In the derivation cohort, both PAMPecho and PCWPecho estimates demonstrated excellent agreement with catheterization measurements. PVRecho was highly feasible, demonstrated negligible bias and excellent agreement with PVRRHC (Bias = −0.58, SD 2.2 mmHg) and outperformed the Abbas method to identify PVRRHC > 3WU (AUC = 0.85 vs. 0.70; p = 0.02). In the validation cohort, PVRecho preserved good invasive agreement with negligible bias, displayed strong diagnostic performance (AUC = 0.84) and significant ability to distinguish isolated post-capillary from combined post- and pre-capillary pulmonary hypertension (PH) subgroups (AUC = 0.77). Conclusion: PVRecho based on Ohm’s law employing pragmatic estimates of PCWPecho demonstrates excellent agreement with invasive reference standard measurements and strong diagnostic ability to identify elevated PVRRHC. This novel approach may be useful during therapy selection to distinguish PH hemodynamic subgroups.

Abstract Aims Echocardiographic predictors of outcomes in heart failure with preserved ejection fraction (HFpEF) have not been systematically or independently validated. We aimed at identifying echocardiographic predictors of cardiovascular events in a large cohort of patients with HFpEF and to validate these in an independent large cohort. Methods and results We assessed the association between echocardiographic parameters and cardiovascular outcomes in 515 patients with heart failure with preserved left ventricular (LV) ejection fraction (>50%) in the MEtabolic Road to DIAstolic Heart Failure (MEDIA) multicentre study. We validated out findings in 286 patients from the Karolinska‐Rennes Prospective Study of HFpEF (KaRen). After multiple adjustments including N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), the significant predictors of death or cardiovascular hospitalization were pulmonary arterial systolic pressure > 40 mmHg, respiratory variation in inferior vena cava diameter > 0.5, E/e' > 9, and lateral mitral annular s' 35% 1 year risk. Adding these four echocardiographic variables on top of clinical variables and NT‐proBNP yielded significant net reclassification improvement (33.8%, P

Background As patients derive variable benefit from generator changes (GCs) of implantable cardioverter‐defibrillators (ICDs) with an original primary prevention (PP) indication, better predictors of outcomes are needed. Methods and Results In the National Cardiovascular Data Registry ICD Registry, patients undergoing GCs of initial non‐cardiac resynchronization therapy PP ICDs in 2012 to 2016, predictors of post‐GC survival and survival benefit versus control heart failure patients without ICDs were assessed. These included predicted annual mortality based on the Seattle Heart Failure Model, left ventricular ejection fraction (LVEF) >35%, and the probability that a patient's death would be arrhythmic (proportional risk of arrhythmic death [PRAD]). In 40 933 patients undergoing GCs of initial noncardiac resynchronization therapy PP ICDs (age 67.7±12.0 years, 24.5% women, 34.1% with LVEF >35%), Seattle Heart Failure Model–predicted annual mortality had the greatest effect size for decreased post‐GC survival (P35% had a lower Seattle Heart Failure Model–adjusted survival versus 23 472 control heart failure patients without ICDs (model interaction hazard ratio, 1.21 [95% CI, 1.11–1.31]). In patients undergoing GCs of initial noncardiac resynchonization therapy PP ICDs with LVEF ≤35%, the model indicated worse survival versus controls in the 21% of patients with a PRAD 65%. The association of the PRAD with survival benefit or harm was similar in patients with or without pre‐GC ICD therapies. Conclusions Patients who received replacement of an ICD originally implanted for primary prevention and had at the time of GC either LVEF >35% alone or both LVEF ≤35% and PRAD

Left ventricular assist devices (LVADs) improve symptoms and outcomes in advanced heart failure. Although device malfunction has decreased significantly with later generation LVADs, it has not been eliminated. We describe the clinical course of a patient with HeartMate 3 LVAD who experienced device malfunction, involving temporary pump shutdown suspected to be caused by electrostatic discharge. (Level of Difficulty: Advanced.)

Abstract Impaired left atrial (LA) function in heart failure with preserved ejection fraction (HFpEF) is associated with adverse outcomes. A subgroup of HFpEF may have LA myopathy out of proportion to left ventricular (LV) dysfunction; therefore, we sought to characterize HFpEF patients with disproportionate LA myopathy. In the prospective, multicenter, Prevalence of Microvascular Dysfunction in HFpEF study, we defined disproportionate LA myopathy based on degree of LA reservoir strain abnormality in relation to LV myopathy (LV global longitudinal strain [GLS]) by calculating the residuals from a linear regression of LA reservoir strain and LV GLS. We evaluated associations of disproportionate LA myopathy with hemodynamics and performed a plasma proteomic analysis to identify proteins associated with disproportionate LA myopathy; proteins were validated in an independent sample. Disproportionate LA myopathy correlated with better LV diastolic function but was associated with lower stroke volume reserve after passive leg raise independent of atrial fibrillation (AF). Additionally, disproportionate LA myopathy was associated with higher pulmonary artery systolic pressure, higher pulmonary vascular resistance, and lower coronary flow reserve. Of 248 proteins, we identified and validated 5 proteins (involved in cardiomyocyte stretch, extracellular matrix remodeling, and inflammation) that were associated with disproportionate LA myopathy independent of AF. In HFpEF, LA myopathy may exist out of proportion to LV myopathy. Disproportionate LA myopathy is a distinct HFpEF subtype associated with worse hemodynamics and a distinct proteomic signature, independent of AF.

AbstractHeart failure with preserved ejection fraction (HFpEF) might soon become the most prevalent type of acute heart failure. Still, despite more than 30 years of research on HFpEF, not only do we lack specific treatment, but also a generally accepted definition of HFpEF. Since 2016, several definitions and algorithms have been proposed for diagnosing both diastolic dysfunction and overt HFpEF. However, all of them focus exclusively on chronic (and not acute) HFpEF. Recent studies showed that acute HFpEF may be overdiagnosed in patients presenting with acute dyspnoea. The aim of our article was to address two questions: (1) why there is a need for specific diagnostic criteria for acute HFpEF, and (2) what such definition of acute HFpEF should encompass.KEY MESSAGES:Several scores and algorithms have been proposed for diagnosing chronic heart failure with preserved ejection fraction (HFpEF), however, so far, there is no definition of acute HFpEF.Acute HFpEF seems to be overdiagnosed in patients presenting with acute dyspnoea.Definition of acute HFpEF should comprise both (1) features of chronic HFpEF and (2) markers of increased left ventricular filling pressures and/or of pulmonary congestion.

Abstract Type 2 diabetes mellitus (T2DM) is highly prevalent in the general population and especially in patients with heart failure (HF). It is not only a risk factor for incident HF, but is also associated with worse outcomes in prevalent HF. Therefore, antihyperglycaemic management in patients at risk of or with established HF is of importance to reduce morbidity/mortality. Following revision of the drug approval process in 2008 by the Food and Drug Administration and European Medicines Agency, several cardiovascular outcome trials on antihyperglycaemic drugs have recently investigated HF endpoints. Signals of harm in terms of increased risk of HF have been identified for thiazolidinediones and the dipeptidyl peptidase 4 inhibitor saxagliptin, and therefore, these drugs are not currently recommended in HF. Sulfonylureas also have an unfavourable safety profile and should be avoided in patients at increased risk of/with HF. Observational studies have assessed the use of metformin in patients with HF, showing potential safety and potential survival/morbidity benefits. Overall use of glucagon‐like peptide 1 receptor agonists has not been linked with any clear benefit in terms of HF outcomes. Sodium–glucose cotransporter protein 2 inhibitors (SGLT2i) have consistently shown to reduce risk of HF‐related outcomes in T2DM with and without HF and are thus currently recommended to lower risk of HF hospitalization in T2DM. Recent findings from the DAPA‐HF trial support the use of dapagliflozin in patients with HF with reduced ejection fraction and, should ongoing trials with empagliflozin, sotagliflozin, and canagliflozin prove efficacy, will pave the way for SGLT2i as HF treatment regardless of T2DM.

Abstract Aims The aim of this study is to study the introduction of sacubitril/valsartan (sac/val) in Sweden with regards to regional differences, clinical characteristics, titration patterns, and determinants of use and discontinuation. Methods and results A national cohort of heart failure was defined from the Swedish Prescribed Drug Register and National Patient Register. A subcohort with additional data from the Swedish Heart Failure Registry (SwedeHF) was also studied. Cohorts were subdivided as per sac/val prescription and registration in SwedeHF. Median sac/val prescription rate was 20 per 100 000 inhabitants. Between April 2016 and December 2017, we identified 2037 patients with ≥1 sac/val prescription, of which 1144 (56%) were registered in SwedeHF. Overall, patients prescribed with sac/val were younger, more frequently male, and had less prior cardiovascular disease than non‐sac/val patients. In SwedeHF subcohort, patients prescribed with sac/val had lower ejection fraction. Overall, younger age [hazard ratio 2.81 (95% confidence interval 2.45–3.22)], registration in SwedeHF [1.97 (1.83–2.12)], male gender [1.50 (1.37–1.64)], ischaemic heart disease [1.50 (1.39–1.62)], lower left ventricular ejection fraction [3.06 (2.18–4.31)], and New York Heart Association IV [1.50 (1.22–1.84)] were predictors for sac/val use. As initiation dose in the sac/val cohort, 38% received 24/26 mg, 54% 49/51 mg, and 9% 97/103 mg. Up‐titration to the target dose was achieved in 57% of the overall cohort over a median follow‐up of 6 months. The estimated treatment persistence for any dose at 360 days was 82%. Conclusions Implementation of sac/val in Sweden was slow and varied five‐fold across different regions; younger age, male, SwedeHF registration, and ischaemic heart disease were among the independent predictors of receiving sac/val. Overall, treatment persistence and tolerability was high.

Abstract Aims A substantial shift in the field of pulmonary hypertension (PH) is ongoing, as the previous practice of mean pulmonary arterial wedge pressure (PAWPM) is no longer supported. Instead, aiming for a better estimate of end‐diastolic pressures (EDP), instantaneous PAWP at mid‐A‐wave (PAWPmid‐A) or, in the absence of an A‐wave, at 130–160 ms following QRS onset has recently been recommended. Electrocardiogram‐gated PAWP (PAWPQRS) has also been proposed. The quantitative differences as well as the diagnostic and prognostic utility of these novel PAWP measurements have not been evaluated. We set out to address these issues. Methods and results Pressure tracings of 141 patients with PH due to left heart disease (PH‐LHD) and 43 with primary pulmonary arterial hypertension (PAH) were analysed. PAWP was measured as follows: (i) mean pressure (PAWPM); (ii) per the latest consensus approach [PAWPmid‐A, or in atrial fibrillation 130, 140, 150, and 160 ms following QRS onset (PAWP130–160)]; (iii) at QRS onset (PAWPQRS); and (iv) Z‐point (PAWPZ). For each PAWP, the corresponding pulmonary vascular resistance (PVR) and diastolic pressure gradient were calculated. The cohort comprised 45% female. Mean age was 66 ± 15. PAWPmid‐A was in good agreement with PAWPZ (17.3 [14.5 to 21.2] vs. 17.6 [14.2 to 21.6] mmHg, P = 0.63), whereas PAWPQRS provided significantly lower values (15.3 [12.5 to 19.2] mmHg, P

Abstract Aims In hospitalized patients with a clinical diagnosis of acute heart failure (HF) with preserved ejection fraction (HFpEF), the aims of this study were (i) to assess the proportion meeting the 2016 European Society of Cardiology (ESC) HFpEF criteria and (ii) to compare patients with restrictive/pseudonormal mitral inflow pattern (MIP) vs. patients with MIP other than restrictive/pseudonormal. Methods and results We included hospitalized participants of the ESC‐Heart Failure Association (HFA) EURObservational Research Programme (EORP) HF Long‐Term Registry who had echocardiogram with ejection fraction (EF) ≥ 50% during index hospitalization. As no data on e', E/e' and left ventricular (LV) mass index were gathered in the registry, the 2016 ESC HFpEF definition was modified as follows: elevated B‐type natriuretic peptide (BNP) (≥100 pg/mL for acute HF) and/or N‐terminal pro‐BNP (≥300 pg/mL) and at least one of the echocardiographic criteria: (i) presence of LV hypertrophy (yes/no), (ii) left atrial volume index (LAVI) of >34 mL/m2), or (iii) restrictive/pseudonormal MIP. Next, all patients were divided into four groups: (i) patients with restrictive/pseudonormal MIP on echocardiography [i.e. with presumably elevated left atrial (LA) pressure], (ii) patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure), (iii) atrial fibrillation (AF) group, and (iv) ‘grey area’ (no consistent description of MIP despite no report of AF). Of 6365 hospitalized patients, 1848 (29%) had EF ≥ 50%. Natriuretic peptides were assessed in 28%, LV hypertrophy in 92%, LAVI in 13%, and MIP in 67%. The 2016 ESC HFpEF criteria could be assessed in 27% of the 1848 patients and, if assessed, were met in 52%. Of the 1848 patients, 19% had restrictive/pseudonormal MIP, 43% had MIP other than restrictive/pseudonormal, 18% had AF and 20% were grey area. There were no differences in long‐term all‐cause or cardiovascular mortality, or all‐cause hospitalizations or HF rehospitalizations between the four groups. Despite fewer non‐cardiac comorbidities reported at baseline, patients with MIP other than restrictive/pseudonormal (i.e. with presumably normal LA pressure) had more non‐cardiovascular (14.0 vs. 6.7 per 100 patient‐years, P

Abstract Aims Left ventricular ejection fraction (EF) is required to categorize heart failure (HF) [i.e. HF with preserved (HFpEF), mid‐range (HFmrEF), and reduced (HFrEF) EF] but is often not captured in population‐based cohorts or non‐HF registries. The aim was to create an algorithm that identifies EF subphenotypes for research purposes. Methods and results We included 42 061 HF patients from the Swedish Heart Failure Registry. As primary analysis, we performed two logistic regression models including 22 variables to predict (i) EF≥ vs.

Abstract Aims In heart failure (HF) with preserved ejection fraction (HFpEF), microvascular inflammation is proposed as an underlying mechanism. Myeloperoxidase (MPO) is associated with vascular dysfunction and prognosis in congestive HF. Methods and results MPO, MPO‐related biomarkers, and echocardiography were assessed in 86 patients, 4–8 weeks after presentation with acute HF (EF ≥ 45%), and in 46 healthy controls. Patients were followed up for median 579 days (Q1;Q3 276;1178) regarding the composite endpoint all‐cause mortality or HF hospitalization. Patients were 73 years old, 51% were female, EF was 64% (Q1;Q3 58;68), E/e′ was ratio 10.8 (8.3;14.0), and left atrial volume index (LAVI) was 43 mL/m2 (38;52). Controls were 60 (57;62) years old (vs. patients; P 14, uric acid and SDMA were elevated (421 vs. 344 μM, P = 0.012; 0.54 vs. 0.47 μM, P = 0.039, respectively), and MPO was 121 vs. 98 ng/mL (P = 0.090). The ratios of arginine/ADMA (112 vs. 162; P

Abstract Aims Neuregulin1‐β (NRG1‐β) is released from microvascular endothelial cells in response to inflammation with compensatory cardioprotective effects. Circulating NRG1‐β is elevated in heart failure (HF) with reduced ejection fraction (HFrEF) but not studied in HF with preserved EF (HFpEF). Methods and results Circulating NRG1‐β was quantified in 86 stable patients with HFpEF (EF ≥45% and N‐terminal pro‐brain natriuretic peptide >300 ng/L), in 86 patients with HFrEF prior to and after left ventricular assist device (LVAD) and/or heart transplantation (HTx) and in 21 healthy controls. Association between NRG1‐β and the composite outcome of all‐cause mortality/HF hospitalization in HFpEF and all‐cause mortality/HTx/LVAD implantation in HFrEF with and without ischaemia assessed as macrovascular coronary artery disease was assessed. In HFpEF, median (25th–75th percentile) NRG1‐β was 6.5 (2.1–11.3) ng/mL; in HFrEF, 3.6 (2.1–7.6) ng/mL (P = 0.035); after LVAD, 1.7 (0.9–3.6) ng/mL; after HTx 2.1 (1.4–3.6) ng/mL (overall P < 0.001); and in controls, 29.0 (23.1–34.3) ng/mL (P = 0.001). In HFrEF, higher NRG1‐β was associated with worse outcomes (hazard ratio per log increase 1.45, 95% confidence interval 1.04–2.03, P = 0.029), regardless of ischaemia. In HFpEF, the association of NRG1‐β with outcomes was modified by ischaemia (log‐rank P = 0.020; Pinteraction = 0.553) such that only in ischaemic patients, higher NRG1‐β was related to worse outcomes. In contrast, in patients without ischaemia, higher NRG1‐β trended towards better outcomes (hazard ratio 0.71, 95% confidence interval 0.48–1.05, P = 0.085). Conclusions Neuregulin1‐β was reduced in HFpEF and further reduced in HFrEF. The opposing relationships of NRG1‐β with outcomes in non‐ischaemic HFpEF compared with HFrEF and ischaemic HFpEF may indicate compensatory increases of cardioprotective NRG1‐β from microvascular endothelial dysfunction in the former (non‐ischaemic HFpEF), but this compensatory mechanism is overwhelmed by the presence of ischaemia in the latter (HFrEF and ischaemic HFpEF).

Abstract Aims The introduction of sacubitril/valsartan (an angiotensin receptor–neprilysin inhibitor) is likely to change the approach to the management of patients with chronic heart failure with reduced ejection fraction (HFrEF). The Assessment of Real Life Care–Describing European Heart Failure Management (ARIADNE) registry will evaluate patient characteristics, practice patterns, outcomes, and healthcare resource utilization in the outpatient setting across Europe, with the main focus on factors that guide physicians' decisions to start and continue sacubitril/valsartan in patients with HFrEF. Methods and results ARIADNE, a prospective, observational registry will enrol 9000 ambulatory patients with HFrEF in 23 European countries Supplement 1. The study will describe 4500 patients treated with conventional treatment (including an angiotensin‐converting enzyme inhibitor/angiotensin receptor blocker), and 4500 patients started on sacubitril/valsartan. In each country, patients will be enrolled consecutively over an expected period of 12 months, and followed‐up for 12 months. The primary objective is to describe the baseline clinical and demographic characteristics of patients with chronic HFrEF, which guide the decision of the treating physician to initiate sacubitril/valsartan or to continue conventional treatment. A co‐primary objective is to identify the baseline characteristics that are associated with the likelihood of reaching the target dose of sacubitril/valsartan 97/103 mg twice daily during follow‐up. Conclusions The ARIADNE registry will provide a comprehensive profile of patients with chronic HFrEF in Europe, will elucidate how management varies between countries, and will help clarify the usage and outcomes associated with use of sacubitril/valsartan in real life.

Abstract Aims Ramp testing in the postoperative period can be used to optimize left ventricular assist device (LVAD) speed for optimal left ventricular (LV) unloading. We tested the hypothesis that a non‐invasive echocardiographic ramp test post‐HeartMate 3 implantation improves LV unloading immediately after and 1–3 months after as compared with before the test. We also tested a secondary hypothesis that speed adjustments during echocardiography‐guided ramp testing do not worsen right ventricular (RV) function immediately after and 1–3 months after. Methods and results We retrospectively reviewed data from patients who underwent an echocardiographic ramp test. A total of 14 out of 19 patients were clinically stable and were enrolled. Adequate LV unloading was defined as no more than mild mitral regurgitation, and intermittent aortic valve (AV) opening or closed AV, and reduction of left ventricular end‐diastolic diameter (LVEDD); and for the follow‐up measurement, decreased NT‐proBNP. Median (interquartile range) time from implantation to ramp test was 27 (16; 56) days, and median time from ramp test to follow‐up echocardiography was 55 (47; 102) days. Median LVAD speed achieved during ramp testing was 5550 (5375; 6025) revolutions per minute (rpm), and median final LVAD speed was 5200 (5000; 5425) rpm. Ramp testing resulted in final LVAD speed increase in 11 (79%) patients and a median net change of 200 (200; 300) rpm. Speed adjustments after ramp testing resulted in improved LVAD unloading that was achieved in additional 3 (21%) patients who were not originally optimized. RV function did not worsen significantly during ramp testing or at final LVAD speed. Conclusions The echocardiographic ramp test allowed LVAD speed adjustment and optimization and improved LV unloading during ramp testing and at final speed with no evidence of worsening of RV function.

Aim: The prognostic value of natriuretic peptides in the management of heart failure (HF) patients with ejection fraction (EF) 40%, HFpEF) managed in primary care. We show that high NT-proBNP predicts increased all-cause mortality in HFpEF-patients managed in primary care. The clinical use is however limited due to large standard deviations, many co-morbidities and high age. Many of these co-morbidities contribute to all-cause mortality and management of these patients should also focus on these co-morbidities.

Abstract Aims This study aims to assess prognostic impact of Framingham criteria for heart failure (FC‐HF) in patients with stable heart failure (HF) with preserved ejection fraction (HFpEF). Methods and results In the prospective Karolinska‐Rennes (KaRen) study, we assessed stable HFpEF patients after an acute HF episode. We evaluated associations between the four descriptive models of HFpEF and the composite endpoint of all‐cause mortality and HF hospitalization. The descriptive models were FC‐HF alone, FC‐HF + natriuretic peptides (NPs) according to the PARAGON trial, FC‐HF + NPs + echocardiographic HFpEF criteria according to European Society of Cardiology HF guidelines, and FC‐HF + NPs + echocardiographic criteria according to the PARAGON trial. Out of the 539 patients enrolled in KaRen, 438 returned for the stable state revisit after 4–8 weeks, 13 (2.4%) patients died before the planned follow‐up, and 88 patients (16%) declined or were unable to return. Three hundred ninety‐nine patients have FC registered at follow‐up, and among these, the four descriptive models were met in 107 (27%), 82 (22%), 61 (21%), and 69 (22%) patients, and not met in 292 (73%). The 107 patients that had FC‐HF at stable state (descriptive model 1) could also be part of the other models because all patients in models 1–4 had to fulfil the FC‐HF. The patients in model 0 did not fulfil the criteria for FC‐HF but could have single FC. Of single FC, only pleural effusion predicted the endpoint [hazard ratio (HR) 3.38, 95% confidence interval (CI) 1.47–7.76, P = 0.004]. Patients without FC‐HF had better prognosis than patients meeting FC‐HF. The unadjusted associations between the four HFpEF descriptive models and the endpoint were HR 1.54, 95% CI 1.14–2.09, P = 0.005; HR 1.71, 95% CI 1.24–2.36, P = 0.002; HR 1.95, 95% CI 1.36–2.81, P = 0.001; and HR 2.05, 95% CI 1.45–2.91, P

Heart failure (HF) represents a global pandemic. Although in HF with reduced ejection fraction (HFrEF) randomized controlled trials have provided effective treatments, prognosis still remains poor, with signals of undertreatment. HF with mid-range EF (HFmrEF) has no evidence-based therapy, and its characterization is ongoing. Trials in HF with preserved EF (HFpEF) have failed to provide any effective treatment, but there are several concerns about their design. Thus, current challenges in the HF field are: 1) optimizing the use of existing treatments in HFrEF; 2) developing and proving efficacy of new treatments, and of new use of existing treatments in HFpEF and HFmrEF. Here we describe how registry-based research can improve knowledge addressing the unmet needs in HF, and in particular we focus on the contribution of the Swedish Heart Failure Registry to this field.