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The article discusses the HF-REVERT trial, which is the first trial to test the efficacy and safety of an antisense oligonucleotide (ASO) in heart failure (HF). The trial focuses on patients with reduced left ventricular ejection fraction (LVEF) after a myocardial infarction (MI). The ASO being tested, CDR132L, suppresses microRNA (miR)-132-3p, which is known to exacerbate adverse cardiac remodeling. The primary endpoint of the trial is the change in echocardiographic left ventricular end-systolic volume index at 6 months. The article highlights the potential of manipulating non-coding RNAs as a new therapeutic strategy for HF. [Extracted from the article]

B This article refers to 'Serial assessment of biomarkers and heart failure outcomes in patients with atrial fibrillation' by K. Oyama I et al i ., published in this issue on pages 832-841. b The incidence and prevalence of atrial fibrillation (AF), by far the most common cardiac arrhythmia, has risen over the last 30 years. Therefore, this data set offers no internal comparison of AF and sinus rhythm with respect to the performance of the three markers in predicting HF hospitalization or HF death. [Extracted from the article]

Cardiac remodelling refers to changes in left ventricular structure and function over time, with a progressive deterioration that may lead to heart failure (HF) development (adverse remodelling) or vice versa a recovery (reverse remodelling) in response to HF treatment. Adverse remodelling predicts a worse outcome, whilst reverse remodelling predicts a better prognosis. The geometry, systolic and diastolic function and electric activity of the left ventricle are affected, as well as the left atrium and on the long term even right heart chambers. At a cellular and molecular level, remodelling involves all components of cardiac tissue: cardiomyocytes, fibroblasts, endothelial cells and leucocytes. The molecular, cellular and histological signatures of remodelling may differ according to the cause and severity of cardiac damage, and clearly to the global trend toward worsening or recovery. These processes cannot be routinely evaluated through endomyocardial biopsies, but may be reflected by circulating levels of several biomarkers. Different classes of biomarkers (e.g. proteins, non‐coding RNAs, metabolites and/or epigenetic modifications) and several biomarkers of each class might inform on some aspects on HF development, progression and long‐term outcomes, but most have failed to enter clinical practice. This may be due to the biological complexity of remodelling, so that no single biomarker could provide great insight on remodelling when assessed alone. Another possible reason is a still incomplete understanding of the role of biomarkers in the pathophysiology of cardiac remodelling. Such role will be investigated in the first part of this review paper on biomarkers of cardiac remodelling. [ABSTRACT FROM AUTHOR]

B This article refers to 'Urinary peptides in heart failure: a link to molecular pathophysiology' by T. He I et al i ., published in this issue on pages 1875-1887. b Proteomic screening of blood and/or urine is gaining prominence as a method to aid discovery of candidate biomarkers to elucidate the molecular basis of disease along with potential applications in clinical diagnosis, risk stratification and treatment decision-making. Urinary peptides in heart failure - the need for care with pees and cues However, whether or not filtration of larger molecular weight peptides out of urine samples (post-sample dilution in SDS containing buffers) also removes bound smaller peptides that could provide extra information remains unknown. [Extracted from the article]

Aims Methods and results Conclusions Soluble fms‐like tyrosine kinase‐1 (sFlt‐1) and placental growth factor (PlGF), components of the vascular endothelial growth factor (VEGF) system, play key roles in angiogenesis. Reports of elevated plasma levels of sFlt‐1 and PlGF in coronary heart disease and heart failure (HF) led us to investigate their utility, and VEGF system gene single nucleotide polymorphisms (SNPs), as prognostic biomarkers in HF.ELISA assays for sFlt‐1, PlGF and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) were performed on baseline plasma samples from the PEOPLE cohort (n = 890), a study of outcomes among patients after an episode of acute decompensated HF. Eight SNPs potentially associated with sFlt‐1 or PlGF levels were genotyped. sFlt‐1 and PlGF were assayed in 201 subjects from the Canterbury Healthy Volunteers Study (CHVS) matched to PEOPLE participants. All‐cause death was the major endpoint for clinical outcome considered. In PEOPLE participants, mean plasma levels for both sFlt‐1 (125 ± 2.01 pg/ml) and PlGF (17.5 ± 0.21 pg/ml) were higher (both p < 0.044) than in the CHVS cohort (81.2 ± 1.31 pg/ml and 15.5 ± 0.32 pg/ml, respectively). sFlt‐1 was higher in HF with reduced ejection fraction compared to HF with preserved ejection fraction (p = 0.005). The PGF gene SNP rs2268616 was univariately associated with death (p = 0.016), and was also associated with PlGF levels, as was rs2268614 genotype. Cox proportional hazards modelling (n = 695, 246 deaths) showed plasma sFlt‐1, but not PlGF, predicted survival (hazard ratio 6.44, 95% confidence interval 2.57–16.1; p < 0.001) in PEOPLE, independent of age, NT‐proBNP, ischaemic aetiology, diabetic status and beta‐blocker therapy.Plasma sFlt‐1 concentrations have potential as an independent predictor of survival and may be complementary to established prognostic biomarkers in HF. [ABSTRACT FROM AUTHOR]

Aim: Pathophysiological differences between patients with heart failure with preserved (HFpEF) and reduced (HFrEF) ejection fraction (EF) remain unclear. Therefore we used a phenomics approach, integrating selected proteomics data with patient characteristics and cardiac structural and functional parameters, to get insight into differential pathophysiological mechanisms and identify potential treatment targets. Methods and results: We report data from a representative subcohort of the prospective Singapore Heart Failure Outcomes and Phenotypes (SHOP), including patients with HFrEF (EF <40%, n = 217), HFpEF (EF ≥50%, n = 213), and age‐ and sex‐matched controls without HF (n = 216). We measured 92 biomarkers using a proximity extension assay and assessed cardiac structure and function in all participants using echocardiography. We used multi‐block projection to latent structure analysis to integrate clinical, echocardiographic, and biomarker variables. Candidate biomarker targets were cross‐referenced with small‐molecule and drug databases. The total cohort had a median age of 65 years (interquartile range 60–71), and 50% were women. Protein profiles strongly discriminated patients with HFrEF (area under the curve [AUC] = 0.89) and HFpEF (AUC = 0.94) from controls. Phenomics analyses identified unique druggable inflammatory markers in HFpEF from the tumour necrosis factor receptor superfamily (TNFRSF), which were positively associated with hypertension, diabetes, and increased posterior and relative wall thickness. In HFrEF, interleukin (IL)‐8 and IL‐6 were possible targets related to lower EF and worsening renal function. Conclusion: We identified pathophysiological mechanisms related to increased cardiac wall thickness parameters and potentially druggable inflammatory markers from the TNFRSF in HFpEF. [ABSTRACT FROM AUTHOR]

2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). For example, among healthy individuals, BNP concentrations average <=10 pg/mL; interestingly, while NT-proBNP concentrations are often much higher than BNP in the presence of prevalent HF, in healthy individuals NT-proBNP is often as very low as BNP. After the first proof of principle for B-type natriuretic peptide (BNP) as a diagnostic aid for acute heart failure (AHF) was reported by Davis I et al i . in 1994,1 the Breathing Not Properly (BNP) study, published in 2002, ushered in a new era for natriuretic peptides (NPs) as companion biomarkers for the diagnosis of heart failure (HF).2 More than just a clinical trial with novel and favourable results, it revolutionized a whole field and introduced biomarkers and the molecular phenotyping of the heart to algorithms in use for HF diagnosis and management. The "Peptide for Life" Initiative: a call for action to provide equal access to the use of natriuretic peptides in the diagnosis of acute heart failure across Europe. [Extracted from the article]

The approval of new heart failure (HF) therapies has slowed over the past two decades in part due to the high costs of conducting large randomized clinical trials that are needed to adequately power major clinical endpoint studies. Several biomarkers have been identified reflecting different elements of HF pathophysiology, with possible applications in diagnosis, risk stratification, treatment monitoring, and even in the design of clinical trials. Biomarkers could potentially be used to refine study inclusion criteria to enable enrolment of patients who are more likely to respond to a therapeutic intervention, despite being at sufficient risk to meet pre‐determined study endpoint rates. When there is a close relationship between biomarker levels and clinical endpoints, changes in biomarker levels after a given treatment can act as a surrogate endpoint, potentially reducing the duration and cost of a clinical trial. Natriuretic peptides have been widely used in clinical trials with a variable amount of added value, which such variation being probably due to the absence of a close pathophysiological connection to the study drug. Notable exceptions to this include sacubitril/valsartan and vericiguat. Future studies should seek to adopt unbiased approaches for discovery of true companion diagnostics; with ‐omics‐based tools, biomarkers might be more precisely selected for use in clinical trials to identify responses that closely reflect the biological effects of the drug under investigation. Finally, biomarkers associated with cardiac damage and remodelling, such as cardiac troponin, could be employed as safety endpoints provided that standardization between different assays is achieved. [ABSTRACT FROM AUTHOR]

Congestion is a cardinal sign of heart failure (HF). In the past, it was seen as a homogeneous epiphenomenon that identified patients with advanced HF. However, current evidence shows that congestion in HF varies in quantity and distribution. This updated view advocates for a congestive‐driven classification of HF according to onset (acute vs. chronic), regional distribution (systemic vs. pulmonary), compartment of distribution (intravascular vs. extravascular), and clinical vs. subclinical. Thus, this review will focus on the utility of circulating biomarkers for assessing and managing the different fluid overload phenotypes. This discussion focused on the clinical utility of the natriuretic peptides, carbohydrate antigen 125 (also called mucin 16), bio‐adrenomedullin and mid‐regional pro‐adrenomedullin, ST2 (also known as interleukin‐1 receptor‐like 1), cluster of differentiation 146, troponin, C‐terminal pro‐endothelin‐1, and parameters of haemoconcentration. The utility of circulation biomarkers on top of clinical evaluation, haemodynamics, and imaging needs to be better determined by dedicated studies. Some multiparametric frameworks in which these tools contribute to management are proposed. [ABSTRACT FROM AUTHOR]

Aim: Different associations between epicardial adipose tissue (EAT) and cardiac function have been suggested in patients with heart failure with preserved (HFpEF) versus reduced and mildly reduced ejection fraction (HFrEF/HFmrEF). However, few studies have directly compared the association between EAT and left atrial (LA) and left ventricular (LV) function in patients with HFpEF and HFrEF/HFmrEF. Methods and results: We studied EAT thickness using transthoracic echocardiography in a multicentre cohort of 149 community‐dwelling controls without heart failure, 99 patients with HFpEF, and 366 patients with HFrEF/HFmrEF. EAT thickness was averaged from parasternal long‐axis and short‐axis views, respectively, and off‐line speckle tracking analysis was performed to quantify LA and LV function. Data were validated in an independent cohort of 626 controls, 243 patients with HFpEF, and 180 patients with HFrEF/HFmrEF. For LV function, LV global longitudinal strain (GLS) was measured in both derivation and validation cohorts. For LA function, LAGLS at reservoir, contractile and conduit phase were measured in the derivation cohort, and only LAGLS at reservoir phase was measured in the validation cohort. In the derivation cohort, EAT thickness was lower in HFrEF/HFmrEF (7.3 ± 2.5 mm) compared to HFpEF (8.3 ± 2.6 mm, p < 0.05) and controls (7.9 ± 1.8 mm, p < 0.05). Greater EAT thickness was associated with better LV and contractile LA function in HFrEF/HFmrEF, but not in HFpEF (p for interaction <0.05). These findings were confirmed in the validation cohort, where EAT thickness was lower in HFrEF/HFmrEF (6.7 ± 1.4 mm) compared to HFpEF (9.6 ± 2.8 mm; p < 0.05) and controls (7.7 ± 2.3 mm; p < 0.05). Greater EAT thickness was associated with better LV and reservoir LA function in patients with HFrEF/HFmrEF but worse LV and reservoir LA function in patients with HFpEF (p for interaction <0.05). Thickened EAT (EAT thickness >10 mm) was associated with LA dysfunction (LAGLS at reservoir phase <23%) in HFpEF, but not in HFrEF/HFmrEF. Conclusion: Epicardial adipose tissue thickness is greater in patients with HFpEF than HFrEF/HFmrEF. Increased EAT thickness is associated with worse LA and LV function in HFpEF but the opposite in HFrEF/HFmrEF. [ABSTRACT FROM AUTHOR]

In patients with heart failure, the beneficial effects of drug and device therapies counteract to some extent ongoing cardiac damage. According to the net balance between these two factors, cardiac geometry and function may improve (reverse remodelling, RR) and even completely normalize (remission), or vice versa progressively deteriorate (adverse remodelling, AR). RR or remission predict a better prognosis, while AR has been associated with worsening clinical status and outcomes. The remodelling process ultimately involves all cardiac chambers, but has been traditionally evaluated in terms of left ventricular volumes and ejection fraction. This is the second part of a review paper by the Study Group on Biomarkers of the Heart Failure Association of the European Society of Cardiology dedicated to ventricular remodelling. This document examines the proposed criteria to diagnose RR and AR, their prevalence and prognostic value, and the variables predicting remodelling in patients managed according to current guidelines. Much attention will be devoted to RR in patients with heart failure with reduced ejection fraction because most studies on cardiac remodelling focused on this setting. [ABSTRACT FROM AUTHOR]

New biomarkers are being evaluated for their ability to advance the management of patients with heart failure. Despite a large pool of interesting candidate biomarkers, besides natriuretic peptides virtually none have succeeded in being applied into the clinical setting. In this review, we examine the most promising emerging candidates for clinical assessment and management of patients with heart failure. We discuss high‐sensitivity cardiac troponins (Tn), procalcitonin, novel kidney markers, soluble suppression of tumorigenicity 2 (sST2), galectin‐3, growth differentiation factor‐15 (GDF‐15), cluster of differentiation 146 (CD146), neprilysin, adrenomedullin (ADM), and also discuss proteomics and genetic‐based risk scores. We focused on guidance and assistance with daily clinical care decision‐making. For each biomarker, analytical considerations are discussed, as well as performance regarding diagnosis and prognosis. Furthermore, we discuss potential implementation in clinical algorithms and in ongoing clinical trials. [ABSTRACT FROM AUTHOR]