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Aims: Heart failure (HF), a global pandemic affecting millions of individuals, calls for adequate predictive guidance for improved therapy. Congestion, a key factor in HF-related hospitalizations, further underscores the need for timely interventions. Proactive monitoring of intracardiac pressures, guided by pulmonary artery (PA) pressure, offers opportunities for efficient early-stage intervention, since haemodynamic congestion precedes clinical symptoms., Methods: The BioMEMS study, a substudy of the MONITOR-HF trial, proposes a multifaceted approach integrating blood biobank data with traditional and novel HF parameters. Two additional blood samples from 340 active participants in the MONITOR-HF trial were collected at baseline, 3-, 6-, and 12-month visits and stored for the BioMEMS biobank. The main aims are to identify the relationship between temporal biomarker patterns and PA pressures derived from the CardioMEMS-HF system, and to identify the biomarker profile(s) associated with the risk of HF events and cardiovascular death., Conclusion: Since the prognostic value of single baseline measurements of biomarkers like N-terminal pro-B-type natriuretic peptide is limited, with the BioMEMS study we advocate a dynamic, serial approach to better capture HF progression. We will substantiate this by relating repeated biomarker measurements to PA pressures. This design rationale presents a comprehensive review on cardiac biomarkers in HF, and aims to contribute valuable insights into personalized HF therapy and patient risk assessment, advancing our ability to address the evolving nature of HF effectively., (© 2024 The Author(s). European Journal of Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

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 < 0.001). A multimarker approach had incremental value beyond a single-marker approach. Our multimarker emergency dyspnea-risk score (MARKED-risk score) incorporating age ≥75 years, systolic blood pressure <110 mm Hg, history of heart failure, dyspnea New York Heart Association functional class IV, hs-cTnT ≥0.04 μg/l, hs-CRP ≥25 mg/l, and Cys-C ≥1.125 mg/l had excellent prognostic performance (area under the curve: 0.85, 95% CI: 0.81 to 0.89), was robust in internal validation analyses and could identify patients with very low (<3 points), intermediate (≥3, <5 points), and high risk (≥5 points) of 90-day mortality (2%, 14%, and 44% respectively; p < 0.001)., 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., (Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. Methods and results: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population‐based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase‐2 (MMP‐2), insulin‐like growth factor binding protein‐2 (IGFBP‐2) and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP‐2 and NT‐proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C‐terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). Conclusion: In individuals without heart failure, LAVi was associated with MMP‐2, IGFBP‐2 and NT‐proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size. [ABSTRACT FROM AUTHOR]

Aim: An echocardiographic algorithm derived by machine learning (e′VM) characterizes pre‐clinical individuals with different cardiac structure and function, biomarkers, and long‐term risk of heart failure (HF). Our aim was the external validation of the e′VM algorithm and to explore whether it may identify subgroups who benefit from spironolactone. Methods and results: The HOMAGE (Heart OMics in AGEing) trial enrolled participants at high risk of developing HF randomly assigned to spironolactone or placebo over 9 months. The e′VM algorithm was applied to 416 participants (mean age 74 ± 7 years, 25% women) with available echocardiographic variables (i.e. e′ mean, left ventricular end‐diastolic volume and mass indexed by body surface area [LVMi]). The effects of spironolactone on changes in echocardiographic and biomarker variables were assessed across e′VM phenotypes. A majority (>80%) had either a 'diastolic changes' (D), or 'diastolic changes with structural remodelling' (D/S) phenotype. The D/S phenotype had the highest LVMi, left atrial volume, E/e', natriuretic peptide and troponin levels (all p < 0.05). Spironolactone significantly reduced E/e' and B‐type natriuretic peptide (BNP) levels in the D/S phenotype (p < 0.01), but not in other phenotypes (p > 0.10; pinteraction <0.05 for both). These interactions were not observed when considering guideline‐recommended echocardiographic structural and functional abnormalities. The magnitude of effects of spironolactone on LVMi, left atrial volume and a type I collagen marker was numerically higher in the D/S phenotype than the D phenotype but the interaction test did not reach significance. Conclusions: In the HOMAGE trial, the e′VM algorithm identified echocardiographic phenotypes with distinct responses to spironolactone as assessed by changes in E/e' and BNP. [ABSTRACT FROM AUTHOR]

Circulating biomarkers and imaging techniques provide independent and complementary information to guide management of heart failure (HF). This consensus document by the Heart Failure Association (HFA) of the European Society of Cardiology (ESC) presents current evidence‐based indications relevant to integration of imaging techniques and biomarkers in HF. The document first focuses on application of circulating biomarkers together with imaging findings, in the broad domains of screening, diagnosis, risk stratification, guidance of treatment and monitoring, and then discusses specific challenging settings. In each section we crystallize clinically relevant recommendations and identify directions for future research. The target readership of this document includes cardiologists, internal medicine specialists and other clinicians dealing with HF patients. [ABSTRACT FROM AUTHOR]

Aims: N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), high‐sensitivity troponin T (hs‐TnT) and soluble suppression of tumorigenesis‐2 (sST2) predict outcome in chronic heart failure (HF). We assessed the influence of age on circulating levels and prognostic significance of these biomarkers. Methods and results: Individual data from 5301 patients with chronic HF and NT‐proBNP, hs‐TnT, and sST2 data were evaluated. Patients were stratified according to age: <60 years (n = 1332, 25%), 60–69 years (n = 1628, 31%), 70–79 years (n = 1662, 31%), and ≥ 80 years (n = 679, 13%). Patients (median age 66 years, 75% men, median left ventricular ejection fraction 28%, 64% with ischaemic HF) had median NT‐proBNP 1564 ng/L, hs‐TnT 21 ng/L, and sST2 29 ng/mL. Age independently predicted NT‐proBNP and hs‐TnT, but not sST2. The best NT‐proBNP and hs‐TnT cut‐offs for 1‐year and 5‐year all‐cause and cardiovascular mortality and 1‐ to 12‐month HF hospitalization increased with age, while the best sST2 cut‐offs did not. When stratifying patients according to age‐ and outcome‐specific cut‐offs, this stratification yielded independent prognostic significance over NT‐proBNP levels only, or the composite of NT‐proBNP and hs‐TnT, and improved risk prediction for most endpoints. Finally, absolute NT‐proBNP, hs‐TnT, and sST2 levels predicted outcomes independent of age, sex, left ventricular ejection fraction category, ethnic group, and other variables. Conclusions: Soluble ST2 is less influenced by age than NT‐proBNP or hs‐TnT; all these biomarkers predict outcome regardless of age. The use of age‐ and outcome‐specific cut‐offs of NT‐proBNP, hs‐TnT and sST2 allows more accurate risk stratification than NT‐proBNP alone or the combination of NT‐proBNP and hs‐TnT. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Aims: Asymptomatic patients with coronary artery disease (CAD), hypertension and/or type 2 diabetes mellitus (T2DM) are at greater risk of developing heart failure (HF). Fibrosis, leading to myocardial and vascular dysfunction, might be an important pathway of progression. The Heart OMics in AGing (HOMAGE) trial aims to investigate the effects of spironolactone on serum markers of collagen metabolism and on cardiovascular structure and function in people at risk of developing HF and potential interactions with a marker of fibrogenic activity, galectin‐3. Methods and results: The HOMAGE trial is a prospective, randomised, open‐label, blinded endpoint (PROBE) study comparing spironolactone (up to 50 mg/day) and standard care over 9 months in people with clinical risk factors for developing HF, including hypertension, CAD and T2DM, and elevated plasma concentrations of N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP, 125 to 1000 ng/L) or B‐type natriuretic peptide (BNP, 35 to 280 ng/L). Exclusion criteria included left ventricular ejection fraction < 45%, atrial fibrillation, severe renal dysfunction, or treatment with loop diuretics. The primary endpoint was the interaction between change in serum concentrations of procollagen type III N‐terminal propeptide (PIIINP) and treatment with spironolactone according to median plasma concentrations of galectin‐3 at baseline. For the 527 participants enrolled, median (interquartile range) age was 73 (69–79) years, 135 (26%) were women, 412 (78%) had hypertension, 377 (72%) CAD, and 212 (40%) T2DM. At baseline, medians (interquartile ranges) were for left ventricular ejection fraction 63 (58–67) %, for left atrial volume index 31 (26‐37) mL/m2, for plasma NT‐proBNP 214 (137–356) ng/L, for serum PIIINP 3.9 (3.1–5.0) ng/mL, and for galectin‐3 16.1 (13.5–19.7) ng/mL. Conclusions: The HOMAGE trial will provide insights on the effect of spironolactone on pathways that might drive progression to HF. Clinical Trial Registration: ClinicalTrials.gov NCT02556450. [ABSTRACT FROM AUTHOR]

Background: Studies on serially measured GDF-15 (growth differentiation factor 15) in acute heart failure (HF) are limited. Moreover, several pathophysiological pathways contribute to HF. Therefore, we aimed to explore the (additional) prognostic value of serially measured GDF-15 using a multi-marker approach to more accurately predict HF risk. Methods: TRIUMPH (Translational Initiative on Unique and Novel Strategies for Management of Patients With Heart Failure) is a prospective cohort of 496 patients with acute HF who were enrolled in 14 hospitals in the Netherlands between 2009 and 2014. Blood sampling was scheduled at 7 moments during 1-year follow-up. GDF-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), ST2 (suppression of tumorigenicity 2), galectin-3, troponin I, and creatinine were measured in a central laboratory. We associated repeated measurements of these biomarkers with the composite primary end point of all-cause mortality and HF rehospitalization, using multivariable joint modeling. Results: Median age was 74 years, and 37% were women. Median baseline GDF-15 was 4632 pg/mL. The primary end point was reached in 188 (40%) patients. The average estimated GDF-15 level increased weeks before the primary end point was reached. The hazard ratio per 1 SD difference in log-GDF-15 was 2.14 (95% CI, 1.78–2.57) unadjusted, 1.96 (1.49–2.53) after adjustment for clinical confounders and 1.44 (1.05–1.91) when jointly modeled with all biomarkers. The adjusted HRs for NT-proBNP were 2.38 (1.78–3.33) and 1.52 (1.15–2.08), respectively. The multimarker model combining GDF-15, NT-proBNP, and troponin I provided a favorable risk discrimination (area under the curve=0.785). Conclusions: Sequentially measured GDF-15 independently and dynamically predicts risk of adverse outcomes during 1-year follow-up after index admission for acute HF. NT-proBNP remains a robust predictor among potential candidates. Multiple biomarkers should be considered for stratification in clinical practice. Registration: URL: https://www.trialregister.nl/trial/1783; Unique Identifier: NTR1893. (The trial can be found temporarily at https://trialsearch.who.int/Trial2.aspx?TrialID=NTR1893.) [ABSTRACT FROM AUTHOR]

Background: Recent clinical studies suggest that inflammatory mediators have huge potential in individualized therapy and in efficacy screening and can be utilized as biomarkers for a plethora of pathological conditions. The standard approach for detecting and measuring these inflammatory mediators is via blood samples. Nevertheless, there is no scientific report providing solid evidence on the most suitable blood compartment that will give the optimal inflammatory mediator measurement, or regarding the diurnal variation of circulating mediators. In this study, we present the biological variability of circulating cytokines and chemokines from healthy individuals (mean age 59 years) assessed by a novel membrane-based assay. Methods: Fifteen males and an equal number of females (all above 50 years) with no known inflammatory condition were selected. Through a planar method, named Proteome Profiler™, improved with fluorescence readout into a semi-quantitative multiplex assay, a screening of 36 inflammatory mediators was performed in serum and plasma of morning and afternoon blood withdrawals. Results: The multiplex analysis revealed that the physiological variability of several circulating inflammatory mediators was relatively small within a cohort of 30 healthy aging subjects. There was no substantial gender effect in the inflammatory mediator profile. On the contrary, most of the cytokine/chemokine values measured in the afternoon collection were found to be higher compared to the morning ones, particularly in plasma. Conclusions: In this study we provide evidence that circulating cytokine and chemokine levels of healthy individuals are elevated when blood is sampled in the afternoon compared to the morning, as influenced by the circulating cortisol levels. Furthermore, we report significant differences between cytokine/chemokine levels measured in serum and plasma. Our results provide essential information for future studies that will focus on examining circulating inflammatory mediator differences between healthy and diseased individuals. [ABSTRACT FROM AUTHOR]

Heart failure is common in older people and its prevalence is increasing. The Heart 'omics' in AGEing (HOMAGE) project aims to provide a biomarker approach that will improve the early diagnosis of heart failure. A large clinical database, based on (1) prospective population studies or (2) cross-sectional, prospective studies or randomized controlled trials (RCTs) of patients at risk for or with overt cardiovascular disease will be constructed to determine most promising 'omics'-based biomarkers to identify the risk of developing heart failure and/or comorbidities. Population studies, patient cohorts and RCTs are eligible for inclusion in the common database, if they received ethical approval to obtain and share data and have baseline information on cardiovascular risk factors. Currently, the HOMAGE database includes 43,065 subjects, from 20 studies in eight European countries, including healthy subjects from three population studies in France, Belgium and Italy (n = 7,124), patients with heart failure (n = 4,312) from four cohorts in the UK, Spain and Switzerland and patients at high risk for cardiovascular disease (n = 31,629) in 13 cohorts. It is anticipated that more partners will join the consortium and enlarge the pooled data. This large merged database will be a useful resource with which to identify candidate biomarkers that play a role in the mechanism underlying the onset and progression of heart failure. [ABSTRACT FROM AUTHOR]

Aims To assess the effects of an NT-proBNP-guided medical management on 18-month outcomes in patients with heart failure (HF) and preserved LVEF ( HFpEF). Methods and results Patients with HFpEF (LVEF >45%; n = 123) and HF with reduced LVEF (HFrEF; LVEF ≤45%; n = 499) with age ≥60 years, NYHA class ≥ II, and elevated NT-proBNP (>400 ng/L or >800 ng/L depending on age) were randomized to medical therapy titrated only to reduce symptoms to NYHA ≤II (symptom-guided) or also to reduce NT-proBNP below the inclusion threshold (NT-proBNP-guided) during a 6-month period. Patients were followed for an additional 12 months. Despite similar treatment escalation, NT-proBNP reduction and symptom relief were less in HFpEF than in HFrEF. Hospitalization-free survival at 18 months was worse in HFpEF than in HFrEF (P = 0.02), while survival and HF hospitalization-free survival did not differ. Among HFpEF patients, NT-proBNP reduction and symptom relief were similar in the symptom-guided (n = 59) and NT-proBNP-guided (n = 64) group despite more aggressive treatment in the NT-proBNP-guided group. In contrast to effects in HFrEF, NT-proBNP-guided management tended to worsen 18-month outcomes in HFpEF, with P-values for the interactions between LVEF stratum and management strategy of 0.2 for hospitalization-free survival, 0.03 for survival, and 0.01 for HF hospitalization-free survival. Conclusions Outcomes in HFpEF were not better than in HFrEF, and opposite effects of NT-proBNP-guided management were observed in HFpEF compared with HFrEF. These preliminary findings suggest that, in contrast to HFrEF, NT-proBNP-guided therapy may not be beneficial in HFpEF. Trial registration ISRCTN43596477. [ABSTRACT FROM AUTHOR]

Background: Soluble suppression of tumorigenesis-2 (sST2) is a biomarker related to inflammation and fibrosis.Objectives: This study assessed the independent prognostic value of sST2 in chronic heart failure (HF).Methods: Individual patient data from studies that assessed sST2 for risk prediction in chronic HF, together with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT), were retrieved.Results: A total of 4,268 patients were evaluated (median age 68 years, 75% males, 65% with ischemic HF, 87% with left ventricular ejection fraction [LVEF] <40%). NT-proBNP, hs-TnT, and sST2 were 1,360 ng/l (interquartile interval: 513 to 3,222 ng/l), 18 ng/l (interquartile interval: 9 to 33 ng/l), and 27 ng/l (interquartile interval: 20 to 39 ng/l), respectively. During a 2.4-year median follow-up, 1,319 patients (31%) experienced all-cause death (n = 932 [22%] for cardiovascular causes). Among the 4,118 patients (96%) with available data, 1,029 (24%) were hospitalized at least once for worsening HF over 2.2 years. The best sST2 cutoff for the prediction of all-cause and cardiovascular death and HF hospitalization was 28 ng/ml, with good performance at Kaplan-Meier analysis (log-rank: 117.6, 61.0, and 88.6, respectively; all p < 0.001). In a model that included age, sex, body mass index, ischemic etiology, LVEF, New York Heart Association functional class, glomerular filtration rate, HF medical therapy, NT-proBNP, and hs-TnT, the risk of all-cause death, cardiovascular death, and HF hospitalization increased by 26%, 25%, and 30%, respectively, per each doubling of sST2. sST2 retained its independent prognostic value across most population subgroups.Conclusions: sST2 yielded strong, independent predictive value for all-cause and cardiovascular mortality, and HF hospitalization in chronic HF, and deserves consideration to be part of a multimarker panel together with NT-proBNP and hs-TnT. [ABSTRACT FROM AUTHOR]