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Aims: It is common practice for clinicians to advise fluid restriction in patients with heart failure (HF), but data from clinical trials are lacking. Moreover, fluid restriction is associated with thirst distress and may adversely impact quality of life (QoL). To address this gap in evidence, the Fluid REStriction in Heart failure vs liberal fluid UPtake (FRESH-UP) study was initiated. Methods: The FRESH-UP study is a randomized, controlled, open-label, multicenter trial to investigate the effects of a 3-month period of liberal fluid intake vs fluid restriction (1500 mL/day) on QoL in outpatients with chronic HF (New York Heart Association Classes II-III). The primary aim is to assess the effect on QoL after 3 months using the Overall Summary Score of the Kansas City Cardiomyopathy Questionnaire (KCCQ). Thirst distress, as assessed by the Thirst Distress Scale for patients with HF, KCCQ Clinical Summary Score, each of the KCCQ domains and clinically meaningful changes in these scores, the EQ-5D-5L, patient-reported fluid intake and safety (ie, death, HF hospitalizations) are secondary outcomes. The FRESH-UP study is registered at ClinicalTrials.gov (NCT04551729). Conclusion: The results of the FRESH-UP study will add substantially to the level of evidence concerning fluid management in chronic HF and may impact the QoL of these patients. Funding Agencies|Dutch Heart Foundation [2019T100]; Radboud University Medical Centre in Nijmegen [R0005106]; Maastricht University Medical Centre [R0005106]

Tweetable abstract #eHealth and #ArtificialIntelligence (AI) bring new possibilities for #HeartFailure (HF) care. We elaborate on potential benefits of #AI in #HF and highlight important bottlenecks for its implementation. #Editorial #Cardiology.

Background Higher body mass index (BMI) is associated with better outcome compared with normal weight in patients with HF and other chronic diseases. It remains uncertain whether the apparent protective role of obesity relates to the absence of comorbidities. Therefore, we investigated the effect of BMI on outcome in younger patients without co-morbidities as compared to older patients with co-morbidities in a large heart failure (HF) population. Methods In an individual patient data analysis from pooled cohorts, 5,819 patients with chronic HF and data available on BMI, co-morbidities and outcome were analysed. Patients were divided into four groups based on BMI (i.e. ≤ 18.5 kg/m2, 18.5–25.0 kg/m2; 25.0–30.0 kg/m2; 30.0 kg/m2). Primary endpoints included all-cause mortality and HF hospitalization-free survival. Results Mean age was 65 ± 12 years, with a majority of males (78%), ischaemic HF and HF with reduced ejection fraction. Frequency of all-cause mortality or HF hospitalization was significantly worse in the lowest two BMI groups as compared to the other two groups; however, this effect was only seen in patients older than 75 years or having at least one relevant co-morbidity, and not in younger patients with HF only. After including medications and N-terminal pro-B-type natriuretic peptide and high-sensitivity cardiac troponin concentrations into the model, the prognostic impact of BMI was largely absent even in the elderly group with co-morbidity. Conclusions The present study suggests that obesity is a marker of less advanced disease, but does not have an independent protective effect in patients with chronic HF. Graphic abstract Categories of BMI are only predictive of poor outcome in patients aged > 75 years or with at least one co-morbidity (bottom), but not in those aged

Aims Whether and how iron deficiency (ID) impacts patients with heart failure (HF) with preserved ejection fraction (HFpEF) remain unclear. The aim of our study was to investigate the impact of ID on functional status, exercise capacity, and prognosis in HFpEF. Methods and results The study population consisted of 300 HFpEF patients. ID was defined as serum ferritin

Aims We sought to compare the generalizability and prognostic implications of heart failure with preserved ejection fraction (HFpEF) scores (HFA-PEFF and H2 FPEF score) in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial participants and matched controls from the Atherosclerosis Risk in Community (ARIC) study. Methods and results Based on the respective scores, the study participants from the TOPCAT (N = 356), RELAX (N = 216), and ARIC (N = 379) studies were categorized as having a low, intermediate, or high likelihood of HFpEF. Age, sex, and race matched controls free of cardiovascular disease who had unexplained dyspnoea were used to evaluate the diagnostic performance. The prognostic value of scores was assessed using multivariable-adjusted Cox regression analyses. The median HFA-PEFF scores in the TOPCAT, RELAX, and ARIC studies were 5.0 [interquartile range (IQR): 5.0-6.0], 4.0 (IQR: 2.0-4.0), and 3.0 (IQR: 2.0-4.0), respectively. The median H2 FPEF scores in the three studies were 5.5 (IQR: 4.0-7.0), 6.0 (IQR: 4.0-7.0), and 3.0 (IQR: 2.0-5.0), respectively. A low HFA-PEFF and H2 FPEF score can rule out HFpEF with high sensitivity (99.5% and 99.6%, respectively) and negative predictive value (95.7% and 98.3%, respectively). A high HFA-PEFF and H2 FPEF score can rule-in HFpEF with good specificity (82.8% and 95.6%, respectively) and positive predictive value (79.9% and 90.4%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H2 FPEF score was 1.26 (95% confidence interval: 0.98-1.63) and 1.01 (95% confidence interval: 0.88-1.15), respectively. A higher H2 FPEF score was associated with lower peak oxygen intake in RELAX trial participants (adjusted P = 0.01). Conclusions The HFA-PEFF and the H2 FPEF scores are reliable diagnostic tools for HFpEF. The prognostic utility of HFpEF scores requires further validation in larger rigorously phenotyped populations.

Background: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. Methods: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. Results: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e′ ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%–35%), E/e′ ratio (18%–29%), tricuspid regurgitation velocity (27%–41%), and tricuspid annular plane systolic excursion (13%) ( P Conclusions: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

European journal of heart failure (2020). doi:10.1002/ejhf.1749, Published by Wiley, Oxford

BACKGROUND: The relationship between longitudinal clinical congestion pattern and heart failure outcome is uncertain. This study was designed to assess the prevalence of congestion over time and to investigate its impact on outcome in chronic heart failure.METHODS: A total of 588 patients with chronic heart failure older than 60 years of age with New York Heart Association (NYHA) functional class >= II from the TIME-CHF study were included. The endpoints for this study were survival and hospitalization-free heart failure survival. Orthopnea, NYHA >= III, paroxysmal nocturnal dyspnea, hepatomegaly, peripheral pitting edema, jugular venous distension, and rales were repeatedly investigated and related to outcomes. These congestion-related signs and symptoms were used to design a 7-item Clinical Congestion Index.RESULTS: Sixty-one percent of patients had a Clinical Congestion Index >= 3 at baseline, which decreased to 18% at month 18. During the median [interquartile range] follow-up of 27.2 [14.3-39.8] months, 17%, 27%, and 47% of patients with baseline Clinical Congestion Index of 0, 1-2, and >= 3 at inclusion, respectively, died (P CONCLUSIONS: The extent of congestion as assessed by means of clinical signs and symptoms decreased over time with intensified treatment, but it remained present or relapsed in a substantial number of patients with heart failure and was associated with poor outcome. This highlights the importance of appropriate decongestion in chronic heart failure. (C) 2019 Elsevier Inc. All rights reserved.

Normal brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) levels are helpful in excluding chronic heart failure in the ambulatory setting, although they have been studied less well and possibly less accurately than in acute care. They may also be of help in screening patients at risk to intervene and reduce the development of heart failure. Natriuretic peptides are also excellent prognostic markers of chronic heart failure, but the clinical value of such prognostic information is less clear. One possible application for this information is guiding medical therapy in chronic heart failure. Many studies have investigated this approach, but results are mixed and do not clearly show improvement in outcome. Still, it may be that in patients with reduced ejection fraction and few comorbidities, measuring NT-proBNP to uptitrate medication improves prognosis.

Aims This study assessed the prognostic implications of mechanical atrial dysfunction in heart failure with preserved ejection fraction (HFpEF) patients with different stages of atrial fibrillation (AF) in detail. Methods and results HFpEF patients (n = 258) systemically underwent an extensive clinical characterization, including 24-h Holter monitoring and speckle-tracking echocardiography. Patients were categorized according to rhythm and stages of AF: 112 with no history of AF (no AF), 56 with paroxysmal AF (PAF), and 90 with sustained (persistent/permanent) AF (SAF). A progressive decrease in mechanical atrial function was seen: left atrial reservoir strain (LASr) 30.5 ± 10.5% (no AF), 22.3 ± 10.5% (PAF), and 13.9 ± 7.8% (SAF), P, Graphical Abstract

Background: β-Blockers (BBs) are mainstay therapy for heart failure with reduced ejection fraction. However, individual patient responses to BB vary, which may be partially due to genetic variation. The goal of this study was to derive and validate the first polygenic response predictor (PRP) for BB survival benefit in heart failure with reduced ejection fraction patients. Methods: Derivation and validation analyses were performed in n=1436 total HF patients of European descent and with ejection fraction Results: Five-fold cross-validation summaries out to 1000 single-nucleotide polymorphisms identified optimal prediction with a 44 single-nucleotide polymorphism score and cutoff at the 30th percentile. In validation testing (n=1188), greater BB exposure was associated with reduced all-cause mortality in patients with low PRP score (n=251; hazard ratio, 0.19 [95% CI, 0.04–0.51]; P =0.0075) but not high PRP score (n=937; hazard ratio, 0.84 [95% CI, 0.53–1.3]; P =0.448)—a difference that was statistically significant ( P interaction, 0.0235). Results were consistent regardless of atrial fibrillation, ejection fraction (≤40% versus 41%–50%), or when examining cardiovascular death. Conclusions: Among patients of European ancestry with heart failure with reduced ejection fraction, a PRP distinguished patients who derived substantial survival benefit from BB exposure from a larger group that did not. Additional work is needed to prospectively test clinical utility and to develop PRPs for other population groups and other medications.

AIM: Diagnosing heart failure with preserved ejection fraction (HFpEF) in the non-acute setting remains challenging. Natriuretic peptides have limited value for this purpose, and a multitude of studies investigating novel diagnostic circulating biomarkers have not resulted in their implementation. This review aims to provide an overview of studies investigating novel circulating biomarkers for the diagnosis of HFpEF and determine their risk of bias (ROB). METHODS AND RESULTS: A systematic literature search for studies investigating novel diagnostic HFpEF circulating biomarkers in humans was performed up until 21 April 2020. Those without diagnostic performance measures reported, or performed in an acute heart failure population were excluded, leading to a total of 28 studies. For each study, four reviewers determined the ROB within the QUADAS-2 domains: patient selection, index test, reference standard, and flow and timing. At least one domain with a high ROB was present in all studies. Use of case-control/two-gated designs, exclusion of difficult-to-diagnose patients, absence of a pre-specified cut-off value for the index test without the performance of external validation, the use of inappropriate reference standards and unclear timing of the index test and/or reference standard were the main bias determinants. Due to the high ROB and different patient populations, no meta-analysis was performed. CONCLUSION: The majority of current diagnostic HFpEF biomarker studies have a high ROB, reducing the reproducibility and the potential for clinical care. Methodological well-designed studies with a uniform reference diagnosis are urgently needed to determine the incremental value of circulating biomarkers for the diagnosis of HFpEF. ispartof: EUROPEAN JOURNAL OF HEART FAILURE vol:22 issue:9 pages:1586-1597 ispartof: location:England status: published

Background It is uncertain whether repeated measurements of a multi-target biomarker panel may help to personalize medical heart failure (HF) therapy to improve outcome in chronic HF. Methods This analysis included 499 patients from the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF), aged ≥ 60 years, LVEF ≤ 45%, and NYHA ≥ II, who had repeated clinical visits within 19 months follow-up. The interaction between repeated measurements of biomarkers and treatment effects of loop diuretics, spironolactone, β-blockers, and renin-angiotensin system (RAS) inhibitors on risk of HF hospitalization or death was investigated in a hypothesis-generating analysis. Generalized estimating equation (GEE) models were used to account for the correlation between recurrences of events in a patient. Results One hundred patients (20%) had just one event (HF hospitalization or death) and 87 (17.4%) had at least two events. Loop diuretic up-titration had a beneficial effect for patients with high interleukin-6 (IL6) or high high-sensitivity C-reactive protein (hsCRP) (interaction, P = 0.013 and P = 0.001), whereas the opposite was the case with low hsCRP (interaction, P = 0.013). Higher dosage of loop diuretics was associated with poor outcome in patients with high blood urea nitrogen (BUN) or prealbumin (interaction, P = 0.006 and P = 0.001), but not in those with low levels of these biomarkers. Spironolactone up-titration was associated with lower risk of HF hospitalization or death in patients with high cystatin C (CysC) (interaction, P = 0.021). β-Blockers up-titration might have a beneficial effect in patients with low soluble fms-like tyrosine kinase-1 (sFlt) (interaction, P = 0.021). No treatment biomarker interactions were found for RAS inhibition. Conclusion The data of this post hoc analysis suggest that decision-making using repeated biomarker measurements may be very promising in bringing treatment of heart failure to a new level in the context of predictive, preventive, and personalized medicine. Clearly, prospective testing is needed before this novel concept can be adopted. Clinical trial registration isrctn.org, identifier: ISRCTN43596477 Electronic supplementary material The online version of this article (10.1007/s13167-018-0137-7) contains supplementary material, which is available to authorized users.

Heart failure is a complex disease with poor outcome. This complexity may prevent care providers from covering all aspects of care. This could not only be relevant for individual patient care, but also for care organisation. Disease management programmes applying a multidisciplinary approach are recommended to improve heart failure care. However, there is a scarcity of research considering how disease management programme perform, in what form they should be offered, and what care and support patients and care providers would benefit most. Therefore, the Improving kNowledge Transfer to Efficaciously Raise the level of Contemporary Treatment in Heart Failure (INTERACT-in-HF) study aims to explore the current processes of heart failure care and to identify factors that may facilitate and factors that may hamper heart failure care and guideline adherence. Within a cross-sectional mixed method design in three regions of the North-West part of Europe, patients (n = 88) and their care providers (n = 59) were interviewed. Prior to the in-depth interviews, patients were asked to complete three questionnaires: The Dutch Heart Failure Knowledge scale, The European Heart Failure Self-care Behaviour Scale and The global health status and social economic status. In parallel, retrospective data based on records from these (n = 88) and additional patients (n = 82) are reviewed. All interviews were audiotaped and transcribed verbatim for analysis.

Background Although heart failure (HF) patients are known to experience repeated hospitalizations, most studies evaluated only time to first event. N-Terminal B-type natriuretic peptide (NT-proBNP)–guided therapy has not convincingly been shown to improve HF-specific outcomes, and effects on recurrent all-cause hospitalization are uncertain. Therefore, we investigated the effect of NT-proBNP–guided therapy on recurrent events in HF with the use of a time-between-events approach in a hypothesis-generating analysis. Methods and Results The Trial of Intensified Versus Standard Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) randomized 499 HF patients, aged ≥60 years, left ventricular ejection fraction ≤45%, New York Heart Association functional class ≥I,I to NT-proBNP–guided versus symptom-guided therapy for 18 months, with further follow-up for 5.5 years. The effect of NT-proBNP–guided therapy on recurrent HF-related and all-cause hospitalizations and/or all-cause death was explored. One hundred four patients (49 NT-proBNP–guided, 55 symptom-guided) experienced 1 and 275 patients (133 NT-proBNP–guided, 142 symptom-guided) experienced ≥2 all-cause hospitalization events. Regarding HF hospitalization, 132 patients (57 NT-proBNP–guided, 75 symptom-guided) experienced 1 and 122 patients (57 NT-proBNP–guided, 65 symptom-guided) experienced ≥2 events. NT-proBNP–guided therapy was significant in preventing 2nd all-cause hospitalizations (hazard ratio [HR] 0.83; P = .01), in contrast to nonsignificant results in preventing 1st all-cause hospitalization events (HR 0.91; P = .35). This was not the case regarding HF hospitalization events (HR 0.85 [P = .14] vs HR 0.73 [P = .01]) The beneficial effect of NT-proBNP–guided therapy was seen only in patients aged

Background Cardiac remodeling and its reversibility are key in HF outcomes. The ST2-R2 score was recently developed to predict relevant left ventricular (LV) reverse remodeling (R2) in patients with heart failure (HF). In the present study we sought to validate the ST2-R2 score for grading improvement in LV ejection fraction (EF) and LV size at one year, and to evaluate its prognostic implication up to 4 years. Methods A total of 569 patients with baseline LVEF < 40% from three international cohorts (Barcelona, TIME-CHF, and PROTECT) were included in the study. Patients were classified into four strata based on their ST2-R2 score, which took into account concentrations of the biomarker ST2, non-ischemic etiology, absence of left bundle branch block, HF duration, baseline LVEF, and β-blocker treatment. Results A significant relationship was observed between ST2-R2 scores and changes in LVEF and indexed LV sizes. LVEF recovery (from + 5.6% to + 17.3%; p < 0.001), percentage reduction in LV end-systolic volume index (from − 6.1% to − 32.1%; p < 0.001) and in LV end-systolic diameter index (from − 1.1% to − 18.6%; p < 0.001) increased over the ST2-R2 strata. A similar trend was observed with diastolic parameters. Improvement in LV function and size was inversely predictive of mortality. Hazard ratios for risk of death, using the lower ST2-R2 score strata (< 9) as a reference, were 0.49 (p < 0.001; score 9–11), 0.27 (p < 0.001; score 12–14), and 0.17 (p < 0.001; score 15–17). Conclusions The ST2-R2 score predicts reverse LV remodeling in HF patients and is useful for predicting mortality up to 4 years.

Background The phenotypically heterogeneous syndrome of heart failure with preserved ejection fraction (HFpEF) is challenging to diagnose. The HFA-PEFF and H2FPEF scores were developed to guide HFpEF diagnosis but have not been directly compared. We evaluated the generalizability and prognostic implications of the two scores in Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) and PDE-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial participants and matched controls from Atherosclerosis Risk in Community (ARIC) study. Methods Participants from TOPCAT, RELAX, and ARIC studies were categorized as having low, intermediate, and high likelihood of HFpEF based on the respective scores. Diagnostic performance was evaluated using age, sex, and race matched controls, free of cardiovascular disease from ARIC study. Multivariable-adjusted Cox regression was used to assess the prognostic value of the scores. Results The median HFA-PEFF score in TOPCAT, RELAX and ARIC was 5.0 (IQR:5.0-6.0), 4.0 (IQR:2.0-4.0) and 3 (IQR:2.0-4.0), respectively. The median H2FPEF score in the three populations was 5.0 (IQR:4.0-7.0), 6.0 (IQR:4.0-7.0), and 2.5 (IQR:2.0-4.0), respectively. High HFA-PEFF scores were seen in 75.8%, 20.4%, and 16.5% of in the three populations, respectively. High H2FPEF scores were seen in 42.3%, 55.3%, and 1.9% of the three populations, respectively. Application of HFA-PEFF score categories to patients categorized using H2FPEF score led to 84.2% of TOPCAT, and 50.5% of RELAX participants being reclassified (Figure 1A,B). Using low HFA-PEFF and H2FPEF scores, HFpEF can be ruled-out with high sensitivity (99.5% and 99.9%, respectively) and high negative predictive value (95.7% and 98.5%, respectively). A high HFA-PEFF and H2FPEF score can rule-in HFpEF with good specificity (83.5% and 98.1%, respectively) and positive predictive value (80.6% and 95.5%, respectively). Among TOPCAT participants, the hazard for adverse cardiovascular events per point increase in HFA-PEFF and H2FPEF score was 1.32 (95% CI: 1.03-1.69) and 1.03 (95% CI: 0.91-1.17), respectively (Figure 1 C,D). Conclusion The HFA-PEFF and the H2FPEF scores are reliable diagnostic tools for HFpEF. The scores also provide prognostic value for the risk stratification of HFpEF patients.

Background: Improvement of left ventricular function (also called left ventricular reverse remodeling [LVRR]) is an important treatment goal in patients with dilated cardiomyopathy (DCM) and hypokinetic non-DCM (HNDC) and is prognostically favorable. We tested whether genetic DCM mutations impact LVRR independent from clinical parameters. Methods and Results: Patients with DCM and hypokinetic non-DCM (n=346; mean left ventricular ejection fraction, 30%) underwent genotyping for 47 DCM-associated genes in addition to extensive phenotyping. LVRR was defined as improvement of left ventricular ejection fraction >50% or ≥10% absolute increase, with cardiac dimensions (left ventricular end diastolic diameter) ≤33 mm/m 2 or ≥10% relative decrease. LVRR occurred in 180 (52%) patients after a median follow-up of 12-month optimal medical treatment. Low baseline left ventricular ejection fraction, a hypokinetic non-DCM phenotype, high systolic blood pressure, absence of a family history of DCM, female sex, absence of atrioventricular block, and treatment with β-blockers were all independent positive clinical predictors of LVRR. With the exception of TTN , genetic mutations were strongly associated with a lower rate of LVRR (odds ratio, 0.19 [0.09–0.42]; P TTN and LMNA were independently associated with LVRR (odds ratio, 2.49 [1.09–6.20]; P =0.038 and 0.11 [0.01–0.99]; P =0.049, respectively). Adding mutation status significantly improved discrimination (C statistics) and reclassification (integrated discrimination improvement/net reclassification index) of the clinical model predicting LVRR. Furthermore, the risk for heart failure hospitalization and cardiovascular death is lower in the LVRR patients on the long term (hazard ratio, 0.47 [0.24–0.91]; P =0.009 and 0.18 [0.04–0.82]; P =0.007, respectively), and LVRR is an independent predictor for event-free survival. Conclusions: The genetic substrate is associated with the clinical course and long-term prognosis of patients with DCM/hypokinetic non-DCM.

BACKGROUND: The GUIDing Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure (GUIDE-IT) trial prospectively compared the efficacy of a NT-proBNP-guided heart failure treatment strategy (target NT-proBNP level

Rationale: To maintain cardiac mechanical and structural integrity after an ischemic insult, profound alterations occur within the extracellular matrix. Osteoglycin is a small leucine-rich proteoglycan previously described as a marker of cardiac hypertrophy. Objective: To establish whether osteoglycin may play a role in cardiac integrity and function after myocardial infarction (MI). Methods and Results: Osteoglycin expression is associated with collagen deposition and scar formation in mouse and human MI. Absence of osteoglycin in mice resulted in significantly increased rupture-related mortality with tissue disruption, intramyocardial bleeding, and increased cardiac dysfunction, despite equal infarct sizes. Surviving osteoglycin null mice had greater infarct expansion in comparison with wild-type mice because of impaired collagen fibrillogenesis and maturation in the infarcts as revealed by electron microscopy and collagen polarization. Absence of osteoglycin did not affect cardiomyocyte hypertrophy in the remodeling remote myocardium. In cultured fibroblasts, osteoglycin knockdown or supplementation did not alter transforming growth factor-β signaling. Adenoviral overexpression of osteoglycin in wild-type mice significantly improved collagen quality, thereby blunting cardiac dilatation and dysfunction after MI. In osteoglycin null mice, adenoviral overexpression of osteoglycin was unable to prevent rupture-related mortality because of insufficiently restoring osteoglycin protein levels in the heart. Finally, circulating osteoglycin levels in patients with heart failure were significantly increased in the patients with a previous history of MI compared with those with nonischemic heart failure and correlated with survival, left ventricular volumes, and other markers of fibrosis. Conclusions: Increased osteoglycin expression in the infarct scar promotes proper collagen maturation and protects against cardiac disruption and adverse remodeling after MI. In human heart failure, osteoglycin is a promising biomarker for ischemic heart failure.

Background: Published studies have generated mixed, controversial results regarding the Cost-effectiveness of heart failure disease management programs (HF-DMPs). This study assessed the cost-effectiveness of an HF-DMP in ambulatory patients compared with usual care (UC).Methods: In the prospective randomized REMADHE trial, we evaluated incremental costs per quality adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 +/- 1.75 years.Results: The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US$7345 (2.5%-97.5% bootstrapped confidence interval similar to 16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY or LY was 99% and 96%, respectively. Cost-effectiveness of HF-DMP was highest in subgroups with left ventricular ejection fraction 50 years, male sex, New York Heart Association (NYHA) functional class >= III, and ischemic etiology. The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY was >= 90% in all subgroups apart from NYHA functional class I-II, where it was 70%. Even when the intervention costs increased by 500% or when excluding outliers in costs, DMP had a high chance of being cost-effective (87%-99%).Conclusions: The HF-DMP of the REMADHE trial, which encompasses long-term repeated education alongside telephone monitoring, has a high probability of being cost-effective in ambulatory patients with HF.

Background— Therapy guided by N-terminal-pro-B-type natriuretic peptide (NT-proBNP) levels may improve outcomes in patients with chronic heart failure (HF), especially in younger patients with reduced left ventricular ejection fraction. It remains unclear whether treatment effects persist after discontinuation of the NT-proBNP–guided treatment strategy. Methods and Results— Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure randomized 499 patients with HF aged ≥60 years with left ventricular ejection fraction ≤45% to intensified, NT-proBNP–guided versus standard, symptom-guided therapy into prespecified age groups (60–74 and ≥75 years) during 18 months. A total of 329 patients (92%) alive at 18 months agreed to long-term follow-up. HF medication was intensified to a larger extent in the NT-proBNP–guided group. During long-term, NT-proBNP–guided therapy did not improve hospital-free (primary end point: hazard ratio, 0.87; 95% confidence interval, 0.71–1.06; P =0.16) or overall survival (hazard ratio, 0.85; 95% confidence interval, 0.64–1.13; P =0.25) but did improve HF hospitalization-free survival (hazard ratio, 0.70; 95% confidence interval, 0.55–0.90; P =0.005). Patients aged 60 to 74 years had benefit from NT-proBNP–guided therapy on the primary end point and HF hospitalization-free survival, whereas patients aged ≥75 years did not ( P Conclusions— Intensified, NT-proBNP–guided therapy did not improve the primary end point compared with symptom-guided therapy but did improve HF hospitalization-free survival. Within the subgroup of patients aged 60 to 74 years, it improved clinical outcome including the primary end point. These effects did not disappear after cessation of the NT-proBNP–guided strategy on the long-term. This is possibly attributable to a more intensified HF medical therapy in the NT-proBNP–guided group. Clinical Trial Registration— URL: http://www.isrctn.org . Unique identifier: ISRCTN43596477.

Aims Heart failure (HF) management is complicated by difficulties in clinical assessment. Biomarkers may help guide HF management, but the correspondence between clinical evaluation and biomarker serum levels has hardly been studied. We investigated the correlation between biomarkers and clinical signs and symptoms, the influence of patient characteristics and comorbidities on New York Heart Association (NYHA) classification and the effect of using biomarkers on clinical evaluation. Methods and results This post-hoc analysis comprised 622 patients (77 ± 8 years, 76 % NYHA class ≥3, 80 % LVEF ≤45 %) participating in TIME-CHF, randomising patients to either NT-proBNP-guided or symptom-guided therapy. Biomarker measurements and clinical evaluation were performed at baseline and after 1, 3, 6, 12 and 18 months. NT-proBNP, GDF-15, hs-TnT and to a lesser extent hs-CRP and cystatin-C were weakly correlated to NYHA, oedema, jugular vein distension and orthopnoea (ρ-range: 0.12–0.33; p

Objectives This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old. Background Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits. Methods In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol. Results NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients l75 years old and in those with l2 significant comorbidities, being dominant in all sensitivity analyses. In the worst-case scenario (excluding residence costs in those with ≥2 comorbidities), the ICER was $11,935 per life-year gained. Conclusions NT-proBNP-guided therapy has a high probability of being cost effective in HF patients with reduced LVEF, particularly in patients age 60 to 75 years or with less than 2 comorbidities. (Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure [TIME-CHF]; ISRCTN43596477 )

BACKGROUND Galectin-3 predicts prognosis in heart failure (HF) and may help to select HF patients in need of intensified therapy. METHODS This retrospective post hoc analysis included 219 patients from the Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure (TIME-HF) and 631 patients from Gruppo Italiano per lo Studio della Sopravvivenza nell'Insufficienza Cardiaca (GISSI-HF) with HF who had reduced ejection fraction and available galectin-3 plasma concentrations. The interaction between galectin-3, β-blockers, renin-angiotensin system (RAS) blockade, and spironolactone on outcome was evaluated in TIME-CHF and validated in GISSI-HF. End points were all-cause mortality and the composite of mortality with HF hospitalization or any hospitalization. RESULTS High galectin-3 concentrations were associated with adverse outcome in both cohorts and remained significantly associated with death after multivariate adjustment [hazard ratio 2.42 (95% CI 1.17–5.01), P = 0.02, in TIME-CHF; 1.47 (1.02–2.10), P = 0.04, in GISSI-HF). In TIME-CHF, patients with low galectin-3 plasma concentrations had a better prognosis when β-blockers were up-titrated, whereas patients with high galectin-3 plasma concentrations did not (interaction P < 0.05 for mortality and death with or without hospitalization). Opposite trends were seen for RAS blockade but were not statistically significant. Patients with high galectin-3 plasma concentrations had neutral prognosis when receiving spironolactone, whereas patients with low galectin-3 plasma concentrations had worse prognosis when receiving spironolactone (interaction P < 0.10 for death with or without hospitalization). In the GISSI-HF validation cohort, these interactions were confirmed for β-blockers (P < 0.05 for all end points) and consistent for RAS blockade (P < 0.10 for death with or without hospitalization), but inconsistent for spironolactone. CONCLUSIONS Galectin-3 is a mediocre prognostic marker, and galectin-3 concentrations interact with the treatment effect of β-blockers and possibly RAS blockade in patients with systolic HF.

Objectives The study aim was to determine the prognostic value of a multimarker strategy for risk-assessment in patients presenting to the emergency department (ED) with dyspnea. Background Combining biomarkers with different pathophysiological backgrounds may improve risk stratification in dyspneic patients in the ED. Methods The study prospectively investigated the prognostic value of the biomarkers N-terminal pro–B-type natriuretic peptide (NT-proBNP), high-sensitivity cardiac troponin T (hs-cTnT), Cystatin-C (Cys-C), high-sensitivity C-reactive protein (hs-CRP), and Galectin-3 (Gal-3) for 90-day mortality in 603 patients presenting to the ED with dyspnea as primary complaint. Results hs-CRP, hs-cTnT, Cyst-C, and NT-proBNP were independent predictors of 90-day mortality. The number of elevated biomarkers was highly associated with outcome (odds ratio: 2.94 per biomarker, 95% confidence interval [CI]: 2.29 to 3.78, p Conclusions A multimarker strategy provided superior risk stratification beyond any single-marker approach. The MARKED-risk score that incorporates hs-cTnT, hs-CRP, and Cys-C along with clinical risk factors accurately identifies patients with very low, intermediate, and high risk.

There is little information regarding the prognostic role of resting heart rate (HR) in older compared with younger patients with chronic heart failure (HF).In patients enrolled in the Trial of Intensified Medical Therapy in Elderly Patients With Congestive Heart Failure (TIME-CHF) with sinus rhythm, effects of baseline HR (≥70 vs70 beats/min [bpm]) on 18-month outcomes were compared between older (≥75 years; n = 186) and younger (75 years; n = 141) patients. Older patients with lower (61 ± 6 bpm) and higher (83 ± 9 bpm) HR had similar left ventricular ejection fraction (LVEF), New York Heart Association (NYHA) functional class, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and survival and HF hospitalization-free survival. In contrast, younger patients with higher HR (81 ± 7 bpm) had higher NT-proBNP and NYHA functional class, lower LVEF, and a higher risk of death (hazard ratio 4.01 [95% confidence interval (CI) 1.17 -13.69]; P = .02) and death or HF hospitalization (hazard ratio 2.35 [95% CI 1.01-5.50]; P = .04) than those with lower HR (62 ± 5 bpm), with the association between higher HR and survival remaining significant after adjustment for NYHA functional class, LVEF, and NT-proBNP.In contrast to HF patients aged75 years, we found no association between HR and worse outcomes in HF patients aged ≥75 years.

This editorial refers to ‘Mid-regional pro-atrial natriuretic peptide and pro-adrenomedullin testing for the diagnostic and prognostic evaluation of patients with acute dyspnoea’, by R.V. Shah et al. , doi:10.1093/eurheartj/ehs136 When patients present with acute dyspnoea, clinicians are faced with relevant issues. Particularly, making the right diagnosis and choosing the best therapies in a timely manner are crucial. To assess the latter, it may help to know the patient's risk, both short and long term, but the direct clinical benefit is less certain. History, physical examination, lab testing, and imaging techniques are cornerstones in order to come to the right conclusions, but they leave important open questions. Biomarkers circulating in the blood are attractive tools to improve care since they represent underlying pathophysiological processes and are relatively easy to measure. However, the question remains of what is their actual role in the clinical setting of acute dyspnoea ( Figure 1 ). Figure 1 Potential clinical usefulness of biomarkers (right-hand side) in the process of heart failure (left-hand side) with respect to diagnosis (green arrows), prognostic assessment (blue arrows), and therapy guidance (yellow arrows). The arrows point to the situation when biomarkers are applicable or of potential benefit. Level of evidence and clinical usefulness: ++, documented in large prospective trials, established, and useful; +, some data, probably useful; ††, well documented, but of unknown clinical benefit; †, less well established, unknown clinical benefit; 0, potential clinical benefit, but little or no data available; aStudy by Shah et al. ;13 brenal markers = serum creatinine, urea, uric acid, and to some extent cystatin C, newer renal markers such as KIM-1, or NGAL which are less well established; ca large number of other biomarkers have been shown to be related to poor outcome,11 of which (hs-)cTnT, haemoglobin, and creatinine are among …

OBJECTIVE: The aim of this work was to assess the prognostic value of absolute N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration in combination with changes during admission because of acute heart failure (AHF) and early after hospital discharge.BACKGROUND: In AHF, readmission and mortality rates are high. Identifying those at highest risk for events early after hospital discharge might help to select patients in need of intensive outpatient monitoring.METHODS AND RESULTS: We evaluated the prognostic value of NT-proBNP concentration on admission, at discharge, 1 month after hospital discharge and change over time in 309 patients included in the PRIMA (Can PRo-brain-natriuretic peptide guided therapy of chronic heart failure IMprove heart fAilure morbidity and mortality?) study. Primary outcome measures were mortality and the combined end point of heart failure (HF) readmission or mortality. In a multivariate Cox regression analysis, change in NT-proBNP concentration during admission, change from discharge to 1 month after discharge, and the absolute NT-proBNP concentration at 1 month after discharge were of independent prognostic value for both end points (hazard ratios for HF readmission or mortality: 1.71, 95% confidence interval [CI] 1.13-2.60, Wald 6.4 [P = .011] versus 2.71, 95% CI 1.76-4.17, Wald 20.5 [P < .001] versus 1.81, 95% CI 1.13-2.89, Wald 6.1 [P = .014], respectively.CONCLUSIONS: Knowledge of change in NT-proBNP concentration during admission because of AHF in combination with change early after discharge and the absolute NT-proBNP concentration at 1 month after discharge allows accurate risk stratification.

Aims NT-proBNP-guided therapy results in intensification of medical heart failure (HF) therapy and is suggested to improve outcome. However, it is feared that an intensified, NT-proBNP-guided therapy carries a risk of adverse effects. Therefore, the safety and tolerability of NT-proBNP-guided therapy in the Trial of Intensified vs standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF) was assessed. Methods and results A total of 495 chronic HF patients, aged ≥60, with an LVEF ≤45%, NYHA class ≥II, randomized to NT-proBNP-guided or symptom-guided therapy and ≥1 month follow-up were included in the present safety analysis. All adverse events (AEs) were recorded during the 18-month trial period. A total of 5212 AEs were noted, 433 of them serious. NT-proBNP-guided therapy led to a higher up-titration of HF medication and was well tolerated, with a dropout rate (12% vs. 11%, P = 1.0) and AE profile [number of AEs/patient-year 4.7 (2.8–9.4) vs. 5.4 (2.7–11.4), P = 0.69; number of severe AEs/patient-year 0.7 (0–2.7) vs. 1.3 (0–3.9), P = 0.21] similar to that of symptom-guided therapy, although most subjects in both treatment groups (96% vs. 95%, P = 0.55) experienced at least one AE. Age and number of co-morbidities were associated with AEs and interacted with the safety profile of NT-proBNP-guided therapy: positive effects were more frequent in younger and less co-morbid patients whereas potential negative effects—although small and related to non-severe AEs only—were only seen in the older and more co-morbid patients. Conclusions NT-proBNP-guided therapy is safe in elderly and highly co-morbid HF patients. Trial registration ISRCTN43596477

This study aimed to assess cost-effectiveness of N-terminal pro-B-type natriuretic peptide (NT-proBNP)-guided versus symptom-guided therapy in heart failure (HF) patients ≥60 years old.Cost-effectiveness of NT-proBNP guidance in HF patients is unclear. It may create additional costs with uncertain benefits.In the TIME-CHF (Trial of Intensified versus Standard Medical Therapy in Elderly Patients with Congestive Heart Failure), patients with left ventricular ejection fraction (LVEF) of ≤45% were randomized to receive intensified NT-proBNP-guided therapy or standard, symptom-guided therapy. For cost-effectiveness analysis, 467 (94%) patients (age 76 ± 7 years, 66% male) were eligible. Incremental cost-effectiveness was calculated as incremental costs per gained life-year and quality-adjusted life-year (QALY) within the 18-month trial period, as defined per protocol.NT-proBNP-guided therapy was dominant (i.e., more effective and less costly) over symptom-guided therapy, saving $2,979 USD (2.5 to 97.5% confidence interval [CI]: $8,758 to $3,265) per patient, with incremental effectiveness of +0.07 life-years and +0.05 QALYs. The probability of NT-proBNP-guided therapy being dominant was 80%, and the probability of saving 1 life-year or QALY at a cost of $50,000 was 97% and 93%, respectively. Exclusion of residence costs resulted in an incremental cost-effectiveness ratio (ICER) of $5,870 per life-year gained. Cost-effectiveness of NT-proBNP-guided therapy was most pronounced in patients 75 years old and in those with2 significant comorbidities, being dominant in all sensitivity analyses. In the worst-case scenario (excluding residence costs in those with ≥2 comorbidities), the ICER was $11,935 per life-year gained.NT-proBNP-guided therapy has a high probability of being cost effective in HF patients with reduced LVEF, particularly in patients age 60 to 75 years or with less than 2 comorbidities. (Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure [TIME-CHF]; ISRCTN43596477).

Purpose: Several studies have shown that heart failure (HF) patients with preserved (HFPEF) versus those with reduced ejection fraction (HFREF) are distinctly different with more comorbidities. They are older, more often female, more likely to have hypertension, atrial fibrillation (AF) and a higher body mass index (BMI). It is unclear to what extent age, gender differences and BMI explain the other differences between HFPEF and HFREF. Methods: All 123 HFPEF patients from TIME-CHF were matched 1:1 to 499 HFREF patients for age (80±7 vs 80±7,P=0.60), gender (66% vs 66% female) and BMI (26.7±5.4 vs 26.7±4.1, P=0.50). Results: HFPEF patients had more frequently hypertension and less frequently coronary artery disease as cause of HF compared to HFREF patients. Number of comorbidities reflected by the Charlson score was similar in both groups. Strikingly, AF was not more common in the HFPEF group. Other specific comorbidities, including COPD, diabetes, stroke, arthritis did also not differ between groups. Symptom severity assessed by NYHA class did also not differ between groups. Laboratory findings including creatinine, urea and liver enzymes were similar in both groups, except for haemoglobin and N-terminal brain natriuretic peptide. The pulse pressure, reflecting arterial stiffness, was significantly higher in HFPEF patients. View this table: Baseline characteristics Conclusion: After matching for age, gender and BMI, prevalence of comorbidities and symptom severity is strikingly similar in HFPEF vs HFREF suggesting that age, gender or BMI may largely explain the differences between HF-groups. This study confirms that hypertension is a more common underlying cause of HFPEF and suggests that vascular stiffness may play a role in pathophysiology of HFPEF.