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Showing papers in "European Journal of Heart Failure in 2016"


Journal ArticleDOI
TL;DR: Authors/Task Force Members: Piotr Ponikowski* (Chairperson) (Poland), Adriaan A. Voors* (Co-Chair person) (The Netherlands), Stefan D. Anker (Germany), Héctor Bueno (Spain), John G. F. Cleland (UK), Andrew J. S. Coats (UK)

13,400 citations


Journal ArticleDOI
TL;DR: No abstract available Keywords: European Society of Cardiology; arrhythmias; cancer therapy; cardio-oncology; cardiotoxicity; chemotherapy; early detection; ischaemia; myocardial dysfunction; surveillance.
Abstract: No abstract available Keywords: European Society of Cardiology; arrhythmias; cancer therapy; cardio-oncology; cardiotoxicity; chemotherapy; early detection; ischaemia; myocardial dysfunction; surveillance.

1,421 citations


Journal ArticleDOI
TL;DR: Novel structured approaches to diagnosis, risk stratification, and management are presented, with new algorithms to aid decision‐making by practising clinicians in the management of complex cases with ongoing symptoms after recovery, recurrent episodes, or spontaneous presentation.
Abstract: 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.

784 citations


Journal ArticleDOI
TL;DR: The prevalence of diastolic dysfunction is on the rise and currently higher than that of systolic dysfunction, and the prevalence of the latter seems to have decreased in the 21st century.
Abstract: The 'epidemic' of heart failure seems to be changing, but precise prevalence estimates of heart failure and left ventricular dysfunction (LVD) in older adults, based on adequate echocardiographic assessment, are scarce. Systematic reviews including recent studies on the prevalence of heart failure and LVD are lacking. We aimed to assess the trends in the prevalence of LVD, and heart failure with reduced (HFrEF) and preserved ejection fraction (HFpEF) in the older population at large. A systematic electronic search of the databases Medline and Embase was performed. Studies that reported prevalence estimates in community-dwelling people ≥60 years old were included if echocardiography was used to establish the diagnosis. In total, 28 articles from 25 different study populations were included. The median prevalence of systolic and 'isolated' diastolic LVD was 5.5% (range 3.3-9.2%) and 36.0% (range 15.8-52.8%), respectively. A peak in systolic dysfunction prevalence seems to have occurred between 1995 and 2000. 'All type' heart failure had a median prevalence rate of 11.8% (range 4.7-13.3%), with fairly stable rates in the last decade and with HFpEF being more common than HFrEF [median prevalence 4.9% (range 3.8-7.4%) and 3.3% (range 2.4-5.8%), respectively]. Both LVD and heart failure remain common in the older population at large. The prevalence of diastolic dysfunction is on the rise and currently higher than that of systolic dysfunction. The prevalence of the latter seems to have decreased in the 21st century.

503 citations


Journal ArticleDOI
TL;DR: 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 with the added intention of comparing differences between countries.
Abstract: 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.

487 citations


Journal ArticleDOI
TL;DR: In the setting of either pressure overload or volume overload, the right ventricular mechanics and function are altered and the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion as mentioned in this paper.
Abstract: Acute right ventricular (RV) failure is a complex clinical syndrome that results from many causes. Research efforts have disproportionately focused on the failing left ventricle, but recently the need has been recognized to achieve a more comprehensive understanding of RV anatomy, physiology, and pathophysiology, and of management approaches. Right ventricular mechanics and function are altered in the setting of either pressure overload or volume overload. Failure may also result from a primary reduction of myocardial contractility owing to ischaemia, cardiomyopathy, or arrhythmia. Dysfunction leads to impaired RV filling and increased right atrial pressures. As dysfunction progresses to overt RV failure, the RV chamber becomes more spherical and tricuspid regurgitation is aggravated, a cascade leading to increasing venous congestion. Ventricular interdependence results in impaired left ventricular filling, a decrease in left ventricular stroke volume, and ultimately low cardiac output and cardiogenic shock. Identification and treatment of the underlying cause of RV failure, such as acute pulmonary embolism, acute respiratory distress syndrome, acute decompensation of chronic pulmonary hypertension, RV infarction, or arrhythmia, is the primary management strategy. Judicious fluid management, use of inotropes and vasopressors, assist devices, and a strategy focusing on RV protection for mechanical ventilation if required all play a role in the clinical care of these patients. Future research should aim to address the remaining areas of uncertainty which result from the complexity of RV haemodynamics and lack of conclusive evidence regarding RV-specific treatment approaches.

433 citations


Journal ArticleDOI
TL;DR: The aim of this study was to assess the net clinical and prognostic effects of intravenous iron therapy in patients with systolic heart failure and iron deficiency.
Abstract: Aims 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). Methods and results 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]. Conclusion 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.

264 citations


Journal ArticleDOI
TL;DR: The role of endothelial dysfunction and inflammation is reviewed to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.
Abstract: Renal dysfunction in heart failure with preserved ejection fraction (HFpEF) is common and is associated with increased mortality. Impaired renal function is also a risk factor for developing HFpEF. A new paradigm for HFpEF, proposing a sequence of events leading to myocardial remodelling and dysfunction in HFpEF, was recently introduced, involving inflammatory, microvascular, and cardiac components. The kidney might play a key role in this systemic process. Renal impairment causes metabolic and systemic derangements in circulating factors, causing an activated systemic inflammatory state and endothelial dysfunction, which may lead to cardiomyocyte stiffening, hypertrophy, and interstitial fibrosis via cross-talk between the endothelium and cardiomyocyte compartments. Here, we review the role of endothelial dysfunction and inflammation to explain the link between renal dysfunction and HFpEF, which allows for identification of new early risk markers, prognostic factors, and unique targets for intervention.

238 citations


Journal ArticleDOI
TL;DR: The aim of this study was to evaluate the prevalence, clinical features, and the independent impact of frailty, a geriatric syndrome characterized by the decline of physiological systems, on prognosis after heart failure hospitalization.
Abstract: Aims The aim of this study was to evaluate the prevalence, clinical features, and the independent impact of frailty—a geriatric syndrome characterized by the decline of physiological systems—and its components, on prognosis after heart failure (HF) hospitalization. Methods and results FRAIL-HF is a prospective cohort study including 450 non-dependent patients ≥70 years old hospitalized for HF. Frailty was screened according to the biological phenotype criteria (low physical activity, weight loss, slow walking speed, weak grip strength, and exhaustion). The independent influence of frailty on mortality, functional decline, and readmission risks was calculated adjusted for HF characteristics and co-morbidities. Mean age was 80 ± 6 years; 76% fulfilled frailty criteria. Frail patients were older, more often female, but showed no differences in chronic co-morbidities, LVEF, and NT-proBNP levels. Slow walking speed was the most discriminative component between frail (89.2%) and non-frail patients (26%). Overall, 1-year survival was 89% in the non-frail group and 75% in frail subjects (P = 0.003). After adjusting for age, gender, chronic and acute co-morbidities, NYHA, and NT-proBNP, frail patients showed higher risks for 30-day functional decline [odds ratio (OR) 2.20, 95% confidence interval (CI) 1.19–4.08], 1-year all-cause mortality [hazard ratio (HR) 2.13, 95% CI 1.07–4.23], and 1-year readmission (OR 1.96, 95% CI 1.14–3.34). The association of individual components with 1-year adjusted mortality risk was HR 2.14, 95% CI 1.05–4.39 for low physical activity and HR 1.77, 95% CI 0.95–3.29 for slow walking speed. Conclusion Frailty is highly prevalent even among non-dependent elderly HF patients, and is an independent predictor of early disability, long-term mortality, and readmission. Individual frailty components may be useful for risk prediction.

226 citations


Journal ArticleDOI
TL;DR: The potential roles of miRNAs as circulating biomarkers and as targets for therapy are reviewed.
Abstract: MicroRNAs (miRNAs) are increasingly recognized to play important roles in cardiovascular diseases, including heart failure. These small, non-coding RNAs have been identified in tissue and are involved in several pathophysiological processes related to heart failure, such as cardiac fibrosis and hypertrophy. As a result, miRNAs have become interesting novel drug targets, leading to the development of miRNA mimics and antimirs. MicroRNAs are also detected in the circulation, and are proposed as potential diagnostic and prognostic biomarkers in heart failure. However, their role and function in the circulation remains to be resolved. Here, we review the potential roles of miRNAs as circulating biomarkers and as targets for therapy.

226 citations


Journal ArticleDOI
TL;DR: To assess physicians' adherence to guideline‐recommended medications for the treatment of chronic heart failure (CHF) with reduced ejection fraction, a randomised, double-blind, placebo-controlled trial is conducted.
Abstract: 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 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.

Journal ArticleDOI
TL;DR: The aim of this study was to compare the long‐term mortality rate of TTC patients with high‐risk patients presenting with ST‐segment elevation myocardial infarction (STEMI).
Abstract: Aims Despite increasing research efforts, the prognostic consequences of takotsubo cardiomyopathy (TTC) remain largely unknown. The aim of this study was therefore to compare the long-term mortality rate of TTC patients with high-risk patients presenting with ST-segment elevation myocardial infarction (STEMI). Methods and results A total of 286 patients with TTC were matched for age and gender with 286 STEMI patients. Outcome was obtained with a standardized telephone follow-up. The primary analysis determined long-term mortality. A secondary analysis was performed evaluating 28-day and 1-year mortality. Follow-up was available for 96% of patients after a mean of 3.8 ± 2.5 years. In TTC patients, long-term mortality was significantly higher compared with the matched STEMI cohort [24.7% vs. 15.1%, hazard ratio (HR) 1.58, 95% confidence interval (CI) 1.07-2.33; P = 0.02]. There was no significant difference in the rates of 28-day (5.5% vs. 5.7%, HR 0.96, 95% CI 0.47-1.94; P = 0.91) and 1-year mortality (12.5% vs. 9%, HR 1.42, 95% CI 0.85-2.38; P = 0.18). In multivariable regression analysis, male sex, a high Killip class on admission, and diabetes mellitus were identified as independent predictors of mortality in TTC patients. A risk score consisting of these factors showed a higher mortality with an increasing number of risk factors. Conclusion Mortality rates in TTC patients are higher than previously expected and long-term mortality exceeded that of patients with STEMI. A simple risk score may provide an approach to identify high-risk patients and predict clinical prognosis.

Journal ArticleDOI
TL;DR: A systematic review and meta‐analysis according to Preferred Reporting Items for Systematic Reviews and Meta‐Analyses on the prevalence and prognostic value of RV dysfunction in heart failure with preserved ejection fraction is conducted.
Abstract: Aims Right ventricular (RV) dysfunction and pulmonary hypertension (PH) are increasingly recognized in heart failure with preserved ejection fraction (HFpEF). The prevalence and prognostic value of RV dysfunction in HFpEF have been widely but variably reported. We therefore conducted a systematic review and meta-analysis according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Methods and results English literature until May 2016 was evaluated for prevalence of RV dysfunction [i.e. tricuspid annular plane systolic excursion (TAPSE) <16 mm, fractional area change (FAC) <35%, or tricuspid annular systolic velocity (RV S') <9.5 cm/s)] and PH [i.e. mean pulmonary artery pressure (MPAP) ≥25 mmHg or pulmonary artery systolic pressure (PASP) ≥35 mmHg]. Combined hazard ratios (HRs) for outcomes were calculated. A total of 38 studies was included. In studies with stringent HFpEF criteria, prevalence of RV dysfunction was 28% for TAPSE, 18% for FAC, and 21% for RV S'. Prevalence of PH was 68% for both increased MPAP and PASP. TAPSE (HR 1.26/5 mm decrease; P < 0.0001), FAC (HR 1.15/5% decrease; P < 0.0001), MPAP (HR 1.26/5 mmHg increase; P < 0.0001), and PASP (1.16/5 mmHg increase; P < 0.0001) were all univariably associated with mortality. HRs for RV S' were not reported. Conclusion RV dysfunction and PH are highly prevalent and are both associated with poor outcome in patients with HFpEF.

Journal ArticleDOI
TL;DR: To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure patients (ejection fraction ≤35%).
Abstract: Aims To assess the tolerability of initiating/uptitrating sacubitril/valsartan (LCZ696) from 50 to 200 mg twice daily (target dose) over 3 and 6 weeks in heart failure (HF) patients (ejection fraction ≤35%). Methods and results A 5-day open-label run-in (sacubitril/valsartan 50 mg twice daily) preceded an 11-week, double-blind, randomization period [100 mg twice daily for 2 weeks followed by 200 mg twice daily (‘condensed’ regimen) vs. 50 mg twice daily for 2 weeks, 100 mg twice daily for 3 weeks, followed by 200 mg twice daily (‘conservative’ regimen)]. Patients were stratified by pre-study dose of angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker (ACEI/ARB; low-dose stratum included ACEI/ARB-naive patients). Of 540 patients entering run-in, 498 (92%) were randomized and 429 (86.1% of randomized) completed the study. Pre-defined tolerability criteria were hypotension, renal dysfunction and hyperkalaemia; and adjudicated angioedema, which occurred in (‘condensed’ vs. ‘conservative’) 9.7% vs. 8.4% (P = 0.570), 7.3% vs. 7.6% (P = 0.990), 7.7% vs. 4.4% (P = 0.114), and 0.0% vs. 0.8% of patients, respectively. Corresponding proportions for pre-defined systolic blood pressure 5.5 mmol/L, and serum creatinine >3.0 mg/dL were 8.9% vs. 5.2% (P = 0.102), 7.3% vs. 4.0% (P = 0.097), and 0.4% vs. 0%, respectively. In total, 378 (76%) patients achieved and maintained sacubitril/valsartan 200 mg twice daily without dose interruption/down-titration over 12 weeks (77.8% vs. 84.3% for ‘condensed’ vs. ‘conservative’; P = 0.078). Rates by ACEI/ARB pre-study dose stratification were 82.6% vs. 83.8% (P = 0.783) for high-dose/‘condensed’ vs. high-dose/‘conservative’ and 84.9% vs. 73.6% (P = 0.030) for low-dose/‘conservative’ vs. low-dose/‘condensed’. Conclusions Initiation/uptitration of sacubitril/valsartan from 50 to 200 mg twice daily over 3 or 6 weeks had a tolerability profile in line with other HF treatments. More gradual initiation/uptitration maximized attainment of target dose in the low-dose ACEI/ARB group.

Journal ArticleDOI
TL;DR: The purpose of this work is to provide an overview of the contribution of major cardiac and non‐cardiac co‐morbidities to HF development and outcomes, in the context of both HFpEF and HFrEF.
Abstract: Several co-existing diseases and/or conditions (co-morbidities) are present in patients with heart failure (HF), with diverse clinical relevance. Multiple mechanisms may underlie the co-existence of HF and co-morbidities, including direct causation, associated risk factors, heterogeneity, and independence. The complex inter-relationship of co-morbidities and their impact on the cardiovascular system contribute to the features of HF, both with reduced (HFrEF) and preserved ejection fraction (HFpEF). The purpose of this work is to provide an overview of the contribution of major cardiac and non-cardiac co-morbidities to HF development and outcomes, in the context of both HFpEF and HFrEF. Accordingly, epidemiological evidence linking co-morbidities to HF and the effect of prevalent and incident co-morbidities on HF outcome will be reviewed.

Journal ArticleDOI
TL;DR: In this analysis, data from PARADIGM‐HF was utilized to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to higher doses of enalapril.
Abstract: Aims In this analysis, we utilized data from PARADIGM-HF to test the hypothesis that participants who exhibited any dose reduction during the trial would have similar benefits from lower doses of sacubitril/valsartan relative to lower doses of enalapril. Methods and results In a post-hoc analysis from PARADIGM-HF, we characterized patients by whether they received the maximal dose (200 mg sacubitril/valsartan or 10 mg enalapril twice daily) throughout the trial or had any dose reduction to lower doses (100/50/0 mg sacubitril/valsartan or 5/2.5/0 mg enalapril twice daily). The treatment effect for the primary outcome was estimated, stratified by dose level using time-updated Cox regression models. In the two treatment arms, participants with a dose reduction (43% of those randomized to enalapril and 42% of those randomized to sacubitril/valsartan) had similar baseline characteristics and similar baseline predictors of the need for dose reduction. In a time-updated analysis, any dose reduction was associated with a higher subsequent risk of the primary event [hazard ratio (HR) 2.5, 95% confidence interval (CI) 2.2–2.7]. However, the treatment benefit of sacubitril/valsartan over enalapril following a dose reduction was similar (HR 0.80, 95% CI 0.70–0.93, P < 0.001) to that observed in patients who had not experienced any dose reduction (HR 0.79, 95% CI 0.71–0.88, P < 0.001). Conclusions In PARADIGM-HF, study medication dose reduction identified patients at higher risk of a major cardiovascular event. The magnitude of benefit for patients on lower doses of sacubitril/valsartan relative to those on lower doses of enalapril was similar to that of patients who remained on target doses of both drugs.

Journal ArticleDOI
TL;DR: The aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF) and to describe the phytochemical hallmarks of these miRNAs.
Abstract: Aims: Our aim was to identify circulating microRNAs (miRNAs) associated with acute heart failure (AHF). Methods and results: Plasma miRNA profiling included 137 patients with AHF from 3 different cohorts, 20 with chronic heart failure (CHF), 8 with acute exacerbation of COPD, and 41 healthy controls. Levels of circulating miRNAs were measured using quantitative reverse transcription–polymerase chain reaction (qRT–PCR). Plasma levels of miRNAs in patients with AHF were decreased compared with CHF patients or healthy subjects, whereas no significant changes were observed between acute COPD patients and controls. Fifteen miRNAs found in the discovery phase to differ most significantly between healthy controls and patients with AHF were further investigated in an extended cohort of 100 AHF patients at admission and a separate cohort of 18 AHF patients at different time points. Out of these 15 miRNAs, 12 could be confirmed in an additional AHF validation cohort and 7 passed the Bonferroni correction threshold (miR-18a-5p, miR-26b-5p, miR-27a-3p, miR-30e-5p, miR-106a-5p, miR-199a-3p, and miR-652-3p, all P < 0.00005). A further drop in miRNA levels within 48 h after AHF admission was associated with an increased risk of 180-day mortality in a subset of the identified miRNAs. Conclusions: Declining levels of circulating miRNAs were associated with increasing acuity of heart failure. Early in-hospital decreasing miRNA levels were predictive for mortality in a subset of miRNAs in patients with AHF. The discovered miRNA panel may serve as a launch-pad for molecular pathway studies to identify new pharmacological targets and miRNA-based therapies.

Journal ArticleDOI
TL;DR: This work aims to provide a history of cardiology in Europe and its applications in the context of women's health and gender identity, as well as some of the conditions leading to female-only cardiology.
Abstract: Johann Bauersachs1,†,*, Mattia Arrigo2,3,†, Denise Hilfiker-Kleiner1, Christian Veltmann1, Andrew J.S. Coats4, Maria G. Crespo-Leiro5, Rudolf A. De Boer6, Peter van der Meer6, Christoph Maack7, Frederic Mouquet8, Mark C. Petrie9, Massimo F. Piepoli10, Vera Regitz-Zagrosek11, Maria Schaufelberger12, Petar Seferovic13, Luigi Tavazzi14, Frank Ruschitzka3, Alexandre Mebazaa15, and Karen Sliwa16 1Department of Cardiology and Angiology, Medical School Hannover, Hannover, Germany; 2Department of Cardiology, AP-HP, Lariboisière University Hospital, Paris, France; 3Department of Cardiology, University Heart Center, University Hospital Zurich, Zurich, Switzerland; 4Monash-Warwick Alliance, Monash University, Australia, and University of Warwick, UK; 5Cardiology Service, Complexo Hospitalario Universitario A Coruña, La Coruña, Spain; 6Department of Cardiology, University Medical Center Groningen, Groningen, The Netherlands; 7Klinik für Innere Medizin III, Universitätsklinikum des Saarlandes, Homburg, Germany; 8Department of Cardiology, Polyclinique du Bois, Lille, France; 9Department of Cardiology, Golden Jubilee National Hospital and Glasgow University, Glasgow, UK; 10Department of Cardiology, Guglielmo da Saliceto Hospital, Piacenza, Italy; 11Institute of Gender in Medicine, Charité Universitaetsmedizin Berlin, and German Center for Cardiovascular Research, Berlin, Germany; 12Section of Acute and Cardiovascular Medicine, Department of Molecular and Clinical Medicine, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sahlgrenska University Hospital/Östra, Gothenburg, Sweden; 13University Medical Center, Belgrade, Serbia; 14Maria Cecilia Hospital, Gruppo Villa Maria Care and Research, Ettore Sansavini Health Science Foundation, Cotignola, Italy; 15Department of Anesthesiology and Critical Care Medicine, AP-HP, Saint Louis Lariboisière University Hospitals, Paris, France; and 16Hatter Institute for Cardiovascular Research in Africa & IDM, Inter-Cape Heart Group, Medical Research Council South Africa, Department of Medicine, University of Cape Town, Cape Town, South Africa

Journal ArticleDOI
TL;DR: To describe the outcomes of pregnancy in women with pulmonary hypertension, a large number of women with this condition are diagnosed with at least some form of pulmonary hypertension during pregnancy.
Abstract: Aims : To describe the outcomes of pregnancy in women with pulmonary hypertension. Methods and results : In 2007 the European Registry on Pregnancy and Heart Disease was initiated by the European Society of Cardiology. Consecutive patients with all forms of cardiovascular disease, presenting with pregnancy, were enrolled with the aim of investigating the pregnancy outcomes. This subgroup of the cohort included 151 women with pulmonary hypertension (PH) either diagnosed by right heart catheterization or diagnosed as possible PH by echocardiographic signs, with 26% having pulmonary arterial hypertension (PAH), in three subgroups: idiopathic (iPAH), associated with congenital heart disease (CHD-PAH), or associated with other disease (oPAH), and 74% having PH caused by left heart disease (LHD-PH, n = 112). Maternal mean age was 29.2 ± 5.6 years and 37% were nulliparous. Right ventricular systolic pressure was 70 mmHg in 11.9%. In more than 75% of patients, the diagnosis of PH had been made before pregnancy. Maternal death up to 1 week after delivery occurred in five patients (3.3%), with another two out of 78 patients who presented for follow-up (2.6%), dying within 6 months after delivery. The highest mortality was found in iPAH (3/7, 43%). During pregnancy, heart failure occurred in 27%. Caesarean section was performed in 63.4% (23.9% as emergency). Therapeutic abortion was performed in 4.0%. Complications included miscarriage (5.6%), fetal mortality (2%), premature delivery (21.7%), low birth weight (19.0%), and neonatal mortality (0.7%). Conclusion : Mortality in this group of patients with various forms of PH was lower than previously reported as specialized care during pregnancy and delivery was available. However, maternal and fetal mortality remains prohibitively high in women with iPAH, although this conclusion is restricted by limited numbers. Early advice on contraception, pregnancy risk and fetal outcome remains paramount.

Journal ArticleDOI
TL;DR: It is hypothesize that individualized therapy is an essential next step to improve outcomes in patients with heart failure.
Abstract: AimsDespite 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. MethodsThe 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. ConclusionBy 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.

Journal ArticleDOI
TL;DR: It is hypothesized that CKD is independently associated with worse cardiac mechanics in HFpEF, and this association is due the effect of CKD on intrinsic abnormalities in cardiac function.
Abstract: Aims Chronic kidney disease (CKD) is associated with worse outcomes in heart failure with preserved ejection fraction (HFpEF). Whether this association is due the effect of CKD on intrinsic abnormalities in cardiac function is unknown. We hypothesized that CKD is independently associated with worse cardiac mechanics in HFpEF. Methods and Results We prospectively studied 299 patients enrolled in the Northwestern University HFpEF Program. Using the creatinine-based CKD-Epi equation to calculate estimated glomerular filtration rate (eGFR), study participants were analysed by CKD status (using eGFR <60 mL/min/1.73 m2 to denote CKD). Indices of cardiac mechanics (longitudinal strain parameters) were measured using speckle-tracking echocardiography. Using multivariable-adjusted linear and Cox regression analyses, we determined the association between CKD and echocardiographic parameters and clinical outcomes (cardiovascular hospitalization or death). Of 299 study participants, 48% had CKD. CKD (dichotomous variable) and reduced eGFR (continuous variable) were both associated with worse cardiac mechanics indices including left atrial (LA) reservoir strain, LV longitudinal strain, and right ventricular free wall strain even after adjusting for potential confounders, including co-morbidities, EF, and volume status. For example, for each 1–SD decrease in eGFR, LA reservoir strain was 3.52% units lower (P < 0.0001) after multivariable adjustment. Reduced eGFR was also associated with worse outcomes [adjusted hazard ratio (HR) 1.28, 95% confidence interval (CI) 1.01–1.61 per 1–SD decrease in eGFR; P = 0.039]. The association was attenuated after adjustment for indices of cardiac mechanics (P = 0.064). Conclusion In HFpEF, CKD is independently associated with worse cardiac mechanics, which may explain why HFpEF patients with CKD have worse outcomes. Trial registration: NCT01030991

Journal ArticleDOI
TL;DR: The transcardiac gradient of 84 cardio‐microRNAs in healthy and failing hearts is evaluated to determine which microRNAs are released or absorbed by the myocardium in heart failure.
Abstract: Aims Differential microRNA expression in peripheral blood has been observed in patients with heart failure, suggesting their value as potential biomarkers and likely contributors to disease mechanisms. In the present study, we aimed to evaluate the transcardiac gradient of 84 cardio-microRNAs in healthy and failing hearts to determine which microRNAs are released or absorbed by the myocardium in heart failure. Methods and results Eight healthy volunteers and nine patients with congestive heart failure were included. Arterial and coronary sinus blood samples were collected, and microRNAs were extracted. The expression of microRNAs was analysed using real-time PCR by the miScript miRNA PCR Array Human Cardiovascular Disease. In coronary sinus samples, the microRNAs miR-16-5p, miR-27a-3p, miR-27b-3p, miR-29b-3p, miR-29c-3p, miR-30e-5p, miR-92a-3p, miR-125b-5p, miR-140-5p, miR-195-5p, miR-424-5p, and miR-451a were significantly down-regulated, and let-7a-5p, let-7c-5p, let-7e-5p, miR-23b-3p, miR-107, miR-155-5p, miR-181a-5p, miR-181b-5p and miR-320a were up-regulated in heart failure. Left ventricular filling pressure was negatively correlated with miR-195, miR-16, miR-29b-3p, miR-29c-3p, miR-451a, and miR-92a-3p. The failing heart released let-7b-5p, let-7c-5p, let-7e-5p, miR-122-5p, and miR-21-5p, and absorbed miR-16-5p, miR-17-5p, miR-27a-3p, miR-30a-5p, miR-30d-5p, miR-30e-5p, miR-130a-3p, miR-140-5p, miR-199a-5p, and miR-451a. In silico analyses suggest that the transcardiac gradient of microRNAs in heart failure may target pathways related to heart disease. Conclusion We determined the transcardiac gradient of cardio-microRNAs in failing hearts, which supports the use of these microRNAs as potential biomarkers. The microRNAs described here may have a role in the pathophysiology of heart failure as they might be involved in pathways related to disease progression, including fibrosis.

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TL;DR: 30‐year nationwide trends in heart failure hospitalization and mortality rates, and the prognostic impact of co‐morbidity, are examined.
Abstract: Aims We examined 30-year nationwide trends in heart failure hospitalization and mortality rates, and the prognostic impact of co-morbidity. Methods and results We conducted a population-based cohort study of 317 161 patients with first-time inpatient hospitalizations for heart failure during 1983–2012. We computed the standardized hospitalization rate and 5-year mortality risk. Co-morbidity levels and calendar periods of diagnosis were compared by means of mortality rate ratios (MRRs) based on Cox regression. The standardized hospitalization rate (per 100 000 persons) decreased between 1983 and 2012 by 25% for women (from 192 to 144) and by 14% for men (from 217 to 186). The decrease reflected an average annual 1% increase until 2000 and a 3.5% decline thereafter. Between 1983–1987 and 2008–2012, 1-year mortality declined from 45% to 33% and 1- to 5-year mortality from 59% to 43%. The decline occurred independently of patients' co-morbidity levels. Comparing 2008–2012 with 1983–1987, the 5-year age-, sex-, and co-morbidity-adjusted MRR was 0.57 [95% confidence interval (CI) 0.56–0.58]. Using low co-morbidity as reference, the adjusted 5-year MRR in 2003–2007 was increased by 43% for moderate, 66% for severe, and 2.2-fold for very severe co-morbidity. The magnitude of co-morbidity-associated mortality increased over time and was highest in the youngest patients. Conclusions Hospitalization rates for heart failure have declined markedly since 2000 in Denmark. One- and five-year mortality declined >40% over the last three decades. The decline in mortality occurred for patients with all levels of co-morbidity, but co-morbidity burden was a strong prognostic factor.

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TL;DR: This study aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction compared with N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), an indicator of haemodynamic wall stress.
Abstract: Aim Growth differentiation factor 15 (GDF15) is a cytokine highly expressed in states of inflammatory stress. We aimed to study the clinical correlates and prognostic significance of plasma GDF15 in heart failure with preserved ejection fraction (HFpEF) vs. reduced ejection fraction(HFrEF), compared with N-terminal pro-brain natriuretic peptide (NT-proBNP), an indicator of haemodynamic wall stress. Methods Plasma GDF15 and NT-proBNP were prospectively measured in 916 consecutive patients with HFrEF (EF <50%; n = 730) and HFpEF (EF ≥50%; n = 186), and measured again at 6 months in 488 patients. Patients were followed up for a composite outcome of death or first HF rehospitalization. Results Median GDF15baseline values were similarly elevated in HFpEF [2862 (1812 represent the 25th percentile and 4176 represent the 75th percentile) ng/L] and HFrEF [2517 (1555, 4030) ng/L] (P = 0.184), whereas NT-proBNP was significantly lower in HFpEF than HFrEF (1119 ng/L vs. 2335 ng/L, P < 0.001). Independent correlates of GDF15baseline were age, systolic blood pressure, New York Heart Association (NYHA) class, diabetes, atrial fibrillation, sodium, haemoglobin, creatinine, diuretic therapy, high sensitivity troponin T (hsTnT) and NT-proBNP (all P < 0.05). During a median follow-up of 23 months, there were 379 events (307 HFrEF, 72 HFpEF). GDF15 remained a significant independent predictor for composite outcome even after adjusting for important clinical predictors including hsTnT and NT-proBNP (adjusted hazard ratio 1.76 per 1 Ln U, 95% confidence interval 1.39–2.21; P < 0.001), regardless of HF group (Pinteraction = 0.275). GDF15baseline provided incremental prognostic value when added to clinical predictors, hsTnT and NT-proBNP (area under receiver operating characteristic curve increased from 0.720 to 0.740, P < 0.019), with a net reclassification improvement of 0.183 (P = 0.004). Patients with ≥20% GDF156months increase had higher risk for composite outcome (adjusted hazard ratio 1.68, 95% confidence interval 1.15–2.45; P = 0.007) compared with those with GDF156months within ± 20% of baseline. Conclusions The similarly elevated levels and independent prognostic utility of GDF15 in HFrEF and HFpEF suggest that beyond haemodynamic stress (NT-proBNP), inflammatory injury (GDF15) may play an important role in both HF syndromes.

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TL;DR: The aim was to study the population‐level distribution and predictors of healthcare expenditure in patients with HF and to establish a clear trend in the cost of HF at a population level.
Abstract: Miguel Cainzos-Achirica was funded by a research grant frorn the Spanish Society of Cardiology.

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TL;DR: The effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin‐induced diabetic mice with diabetes mellitus are evaluated.
Abstract: Aims Angiotensin receptor–neprilysin inhibitors (ARNis) acts an ARB and neprilysin inhibitor. Diabetes mellitus significantly increases the risk of cardiovascular disease and heart failure (HF). Therefore, we evaluated the effects and mechanisms of ARNi in HF with reduced ejection fraction (HFrEF) in streptozotocin-induced diabetic mice. Methods and results Male C57BL/6J mice were injected with streptozotocin to produce diabetic mice. After myocardial reperfusion injury, diabetic mice were randomized to treatment for 4 weeks with LCZ696 (60 mg/kg), valsartan (30 mg/kg), or no treatment (n = 26–28 in each group). Cardiac function was assessed by a pressure–volume Millar catheter. The ratios of heart weight to body weight in the valsartan (P = 0.02) and LCZ696 (P = 0.005) groups were significantly less than that in the control group. Treatment with LCZ696 improved LVEF (43 ± 3.4%) with a significantly reduction of atrial natriuretic peptide mRNA in the left ventricle compared with that in the control group (29 ± 3.2%) (P = 0.006). The fibrotic area in the LCZ696 group was significantly suppressed compared with those in the control (P = 0.003) and valsartan (P = 0.04) groups. Moreover, the mRNA level of transforming growth factor-β (TGF-β) in the left ventricle was suppressed in the LCZ696 group compared with that in the control (P = 0.002) group. Conclusion The ARNi LCZ696 improved cardiac function with the reduction of fibrosis in an HF-rEF model in diabetic mice, by suppressing TGF-β. This effect may be due to the specific inhibition of neprilysin, beyond the ARB effect of LCZ696.

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TL;DR: Patients with heart failure randomized in controlled trials are generally selected and do not fully represent the ‘real world’, so administrative data of nearly 2 500 000 subjects is analysed to better describe the characteristics of HF.
Abstract: Aims Patients with heart failure (HF) randomized in controlled trials are generally selected and do not fully represent the ‘real world’. The purpose of this study is to better describe the characteristics of HF by analysing administrative data of a population of nearly 2 500 000 subjects. Methods and results Data came from the ARNO Observatory including inhabitants of five Local Health Units of the Italian National Health Service (INHS). Patients were selected when discharged for HF (1 January 2008–31 December 2012) and prescribed at least one HF treatment. Clinical characteristics, pharmacological treatments, rehospitalization, and direct costs for the INHS were described during 1-year follow-up (FU). Of the 2 456 739 subjects included in the database, 54 059 (2.2%) were hospitalized for HF: 41 413 were discharged alive and prescribed HF treatments. Mean age was 78 ± 11 years and 51.4% were females. Just 26.6% were managed in a cardiology setting. The most frequent co-morbidities were diabetes (30.7%), COPD (30.5%), and depression (21%). ACE inhibitors/ARBs, beta-blockers, and mineralocorticoid antagonists were prescribed in 65.8, 49.7, and 42.1% of patients, respectively. During 1-year FU, at least one rehospitalization occurred in 56.6% of patients, 49% of them due to non-cardiovascular causes. The direct cost per patient per year to the INHS was €11 867, of which 76% was related to hospitalizations. Conclusions Real-world evidence provides a description of patient characteristics and treatment patterns that are different from those reported by randomized clinical trials. Costs for the INHS are mainly driven by hospitalizations, which are often due to non-cardiovascular reasons.

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TL;DR: Assessment of the incidence and risk of cancer and all‐cause mortality in a large Danish HF cohort found that co‐morbidity is increasing and improving with improvement in survival of chronic heart failure.
Abstract: Aims With improvement in survival of chronic heart failure (HF), the clinical importance of co-morbidity is increasing. The aim of this study was to assess the incidence and risk of cancer and all-cause mortality in a large Danish HF cohort. Methods and results A total of 9307 outpatients with verified HF without a prior diagnosis of cancer (27% female, mean age 68 years, 89% with LVEF <45%) were included in the study. A diagnosis of any cancer and all-cause mortality was obtained from Danish national registries. Outcome was compared with the general Danish population. Overall and type-specific risk of cancer was analysed in an adjusted Poisson and Cox regression analysis. The 975 diagnoses of cancer in the HF cohort and 330 843 in the background population corresponded to incidence rates per 10 000 patient-years of 188.9 [95% confidence interval (CI) 177.2–200.6] and 63.0 (95% CI 63.0–63.4), respectively. When stratified by age, incidence rates were increased in all age groups in the HF cohort. Risk of any type of cancer was increased, with an incidence rate ratio of 1.24 (95% CI 1.15–1.33, c < 0.0001). Type-specific analysis demonstrated an increased hazard ratio for all major types of cancer except for prostate cancer. All-cause mortality was higher in HF patients with cancer compared with cancer patients from the background population. Conclusion Patients with HF have an increased risk of cancer, which persists after the first year after the diagnosis of HF, and their prognosis is worse compared with that of cancer patients without HF.

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TL;DR: In heart failure with reduced ejection fraction, drug and device therapy improve survival and contemporary trends in utilization of evidence‐based therapy and associated survival are studied.
Abstract: Aims In heart failure with reduced ejection fraction, drug and device therapy improve survival. We studied contemporary trends in utilization of evidence-based therapy and associated survival. Methods and results We studied 5908 patients with NYHA class II–IV heart failure, EF <30%, and duration of heart failure ≥6 months registered in the Swedish Heart Failure Registry between 2003 and 2012. Regression using generalized estimation equations was used to examine temporal trends in crude and risk-adjusted rates of utilization of evidence-based heart failure therapy and 30-day, 1-year, and 3-year survival. In 2003 vs. 2012, the risk-adjusted use of therapy and P-values for trends were as follows: renin–angiotensin system antagonists, 88% vs. 86% (P = 0.091); beta-blockers, 85% vs. 93% (P = 0.008); mineralocorticoid receptor antagonists, 53% vs. 42% (P < 0.001); CRT, 2.4% vs. 8.2% (P = 0.074); and implantable cardioverter-defibrillators, 4.0% vs. 10.7% (P = 0.004). During the same period, the risk-adjusted 30-day, 1-year, and 3-year survival was 92% vs. 94% (P = 0.532), 81% vs. 77% (P = 0.260), and 58% vs. 54% (P = 0.425), respectively. Conclusions In this large nationwide registry, over the last decade the use of evidence-based drug therapy was high and remained stable over time, but, despite an increased use of device therapy, the absolute use was poor. This was associated with an absence of improvement in survival. The improvements in therapy and prognosis over the last generation may be levelling off, and efforts should be directed at improving implementation of evidence-based therapy.

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TL;DR: The hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure is tested.
Abstract: Aims AUGMENT-HF was an international, multicentre, prospective, open-label, randomized, controlled evaluation testing the hypothesis that Algisyl (injectable calcium alginate hydrogel) is superior to standard medical therapy (SMT) for improving functional capacity and clinical outcomes in patients with advanced heart failure (HF). We previously reported results following 6 months of follow-up. This report presents the results from 1 year of extended follow up for this clinical trial. Methods and results We enrolled 78 patients with advanced HF, randomized (1:1), to Algisyl with SMT or SMT alone as previously reported. Patient inclusion criteria were LVEF ≤35%, peak VO2 of 9.0–14.5 mL/min/kg and LV end-diastolic diameter (LVEDD) index 30–40 mm/m2 (LVEDD/body surface area). Patients must have been on stable, evidence-based therapy for HF. A total of 58 patients, mean age 62.3 ± 9.6 years, with ischaemic (57.7%) or non-ischaemic (42.3%) HF completed 12 months of follow-up. Treatment with Algisyl was associated with improved peak VO2 at 12 months; treatment effect vs. control of +2.10 mL/kg/min (95% confidence interval 0.96–3.24, P < 0.001). Statistically significant improvements were observed for VO2 at anaerobic threshold, 6-min walk test distance, and NYHA functional class (all P < 0.001). Through 12 months of follow-up there were 4 (10.5%) deaths in the control group and 9 (22.5%) deaths in the Algisyl group. Conclusions Algisyl in addition to SMT was more effective than SMT alone for providing sustained 1-year benefits in exercise capacity, symptoms, and clinical status for patients with advanced HF. These data support larger clinical evaluations of this novel therapy.