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Aims: The PARACOR-19 randomized controlled trial (RCT) was designed to examine the effects of sacubitril/valsartan on markers of cardiac injury, inflammation, structure, and function among patients who have recovered from acute coronavirus disease 2019 (COVID-19) infection., Methods and Results: PARACOR-19 was a single-centre, double-blind RCT of patients with cardiovascular risk factors and a history of COVID-19 infection 4-16 weeks prior to enrolment. Patients were randomized to sacubitril/valsartan (titrated to the maximum dose of 97/103 mg twice daily) versus matching placebo. Co-primary endpoints were change from baseline to 12 weeks in high-sensitivity cardiac troponin T (hs-cTnT) and soluble ST2 (sST2). Exploratory endpoints included change from baseline to 12 weeks in additional circulating biomarkers. Overall, 42 patients were randomized between August 2021 and March 2023 (n = 20 sacubitril/valsartan, n = 22 placebo). Median (25th-75 th ) time from COVID-19 diagnosis to enrolment was 67 (48-80) days. Median age was 67 (62-71) years, 48% were female, and 91% were White. Compared with placebo, sacubitril/valsartan did not have a significant effect on the co-primary endpoints of change from baseline in hs-TnT and sST2 (all p ≥ 0.29). In exploratory analyses, sacubitril/valsartan led to a 46% greater reduction in N-terminal pro-B-type natriuretic peptide (NT-proBNP) and 51% greater reduction in C-terminal telopeptide of collagen type I (CITP). Permanent drug discontinuation occurred in four patients in the sacubitril/valsartan group and three patients in the placebo group. There were no deaths and one patient was hospitalized in each group., Conclusion: In this pilot RCT of patients who recovered from acute COVID-19, sacubitril/valsartan did not lower hs-cTnT or sST2 compared with placebo. Exploratory analyses suggested potential benefits of sacubitril/valsartan on cardiac wall stress and collagen turnover as measured by NT-proBNP and CITP. Sacubitril/valsartan was well tolerated., Clinical Trial Registration: ClinicalTrials.gov NCT04883528., (© 2024 European Society of Cardiology.)

Background: Omecamtiv mecarbil improves outcomes in patients with heart failure and reduced ejection fraction (HFrEF). We examined the relationship between baseline troponin levels, change in troponin levels over time and the treatment effect of omecamtiv mecarbil in patients enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes through Improving Contractility in Heart Failure (GALACTIC-HF) trial (NCT02929329)., Methods: GALACTIC-HF was a double-blind, placebo-controlled trial that randomized 8256 patients with symptomatic HFrEF to omecamtiv mecarbil or placebo. High-sensitivity troponin I (cTnI) was measured serially at a core laboratory. We analyzed the relationship between both baseline cTnI and change in cTnI concentrations with clinical outcomes and the treatment effect of omecamtiv mecarbil., Results: Higher baseline cTnI concentrations were associated with a risk of adverse outcomes (hazard ratio for the primary endpoint of time to first HF event or CV death = 1.30; 95% CI 1.28, 1.33; P < 0.001 per doubling of baseline cTnI). Although the incidence of safety outcomes was higher in patients with higher baseline cTnI, there was no difference between treatment groups. Treatment with omecamtiv mecarbil led to a modest increase in cTnI that was related to plasma concentrations of omecamtiv mecarbil, and it peaked at 6 weeks. An increase in troponin from baseline to week 6 was associated with an increased risk of the primary endpoint (P < 0.001), which was similar, regardless of treatment assignment (P value for interaction = 0.2)., Conclusions: In a cohort of patients with HFrEF, baseline cTnI concentrations were strongly associated with adverse clinical outcomes. Although cTnI concentrations were higher in patients treated with omecamtiv mecarbil, we did not find a differential effect of omecamtiv mecarbil on either safety or efficacy based on baseline cTnI status or change in cTnI., Competing Interests: DISCLOSURES GMF has received research grants from NHLBI, American Heart Association, Amgen, Bayer, BMS, Merck, Cytokinetics, and CSL-Behring; he has acted as a consultant to Novartis, Amgen, BMS, Cytokinetics, Medtronic, Cardionomic, Boehringer-Ingelheim, American Regent, Abbott, Astra-Zeneca, Reprieve, Myovant, Sequana, Windtree Therapuetics, and Whiteswell and has served on clinical endpoint committees/data safety monitoring boards for Amgen, Merck, Medtronic, EBR Systems, V-Wave, LivaNova, Siemens, and Rocket Pharma. SDS reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study; grants (via Brigham and Women's Hospital) from Actelion, Alnylam Pharmaceuticals, Amgen, AstraZeneca, Bellerophon Therapeutics, Bayer, Bristol Myers Squibb, Celladon, Cytokinetics, Eidos Therapeutics, Eli Lilly, Gilead Sciences,GlaxoSmithKline, Ionis Pharmaceuticals, Mesoblast,Myocardium, the National Heart, Lung, and Blood Institute, NeuroTronik, Novartis, Novo Nordisk, Respicardia, Sanofi Pasteur, and Theracos; and consulting fees from Abbott Laboratories, Action Pharma, Akros Pharma, Alnylam Pharmaceuticals, American Regent, Amgen, Arena Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Cardiac Dimensions, Cardior Pharmaceuticals, Cardurion Pharmaceuticals, CellProthera, Corvia Medical, Cytokinetics, Daiichi Sankyo, Dinaqor, Eli Lilly and Company, GlaxoSmithKline, Janssen Pharmaceuticals, Merck & Co, Moderna, Myokardia, Novartis, Quantum Genomics, Roche, Sanofi Pasteur, Sarepta Therapeutics, Tenaya Therapeutics, Theracos, and Tremeau Pharmaceuticals. MM reports receiving personal fees from Amgen and Servier Laboratories during the conduct of the study and personal fees from Abbott Laboratories, Actelion, AstraZeneca, Edwards Lifesciences, LivaNova, Vifor Pharma, and Windtree Therapeutics. JJVM reports receiving travel fees and nonfinancial support (via the University of Glasgow) from Amgen during the conduct of the study; travel fees and nonfinancial support (via the University of Glasgow) from Alnylam Pharmaceuticals, AstraZeneca, Bayer, Bristol Myers Squibb, Cyclerion Therapeutics, Cytokinetics, DalCor Pharmaceuticals, GlaxoSmithKline, Novartis, Pfizer, Servier Laboratories, and Theracos; and personal fees from Abbott Laboratories, Hikma Pharmaceuticals, Servier Laboratories, and Sun Pharmaceutical Industries. RD reports receiving grants from Amgen during the conduct of the study. BC reports receiving grants (via Brigham and Women's Hospital) from Amgen and Cytokinetics during the conduct of the study and consulting fees from Amgen, Boehringer Ingelheim, Corvia Medical, Myokardia, and Novartis. DEL is supported in part by grants from the National Institutes of Health (P50MD017351, R01HL132154), has received research funding or support from Amgen, Astra Zeneca, Janssen, Eli Lilly, and Somalogic, and has acted as consultant to ACI Clinical (Abbott Laboratories), AstraZeneca, Cytokinetics, Duke Clinical Research Institute (CONNECT-HF), Illumina, Janssen, Martin Pharmaceuticals, Ortho Clinical Diagnostics, and Otsuka. HV reports being a national leader of GALACTIC-HF and has received lecture fees and consultation fees from Amgen. RDL reports research grants or contracts from Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, Sanofi-Aventis and funding for educational activities or lectures from Pfizer and Daiichi Sankyo and funding for consulting or other services from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, and Novo Nordisk. S-IM reports being a national leader of GALACTIC-HF and has received lecture and consultation fees from Amgen. TB-S reports being a steering committee member of the Amgen-financed GALACTIC-HF trial, chief investigator and steering committee chair of the Sanofi Pasteur-financed NUDGE-FLU trial; chief investigator and steering committee chair of the Sanofi Pasteur-financed DANFLU-1 trial; steering committee member of LUX-Dx TRENDS Evaluates Diagnostics Sensors in Heart Failure Patients Receiving Boston Scientific's Investigational ICM System trial; is on the advisory boards of Sanofi Pasteur, Amgen and GSK; receives speaker honoraria from Bayer, Novartis, Sanofi Pasteur, and GSK and research grants from GE Healthcare and Sanofi Pasteur. SBH, PHD, SK, and FIM are employees of Cytokinetics. JRT reports receiving grants from Amgen and Cytokinetics, personal fees from Amgen, Cytokinetics and Servier Laboratories, and nonfinancial support from Amgen and Cytokinetics during the conduct of the study; grants from Abbott Laboratories, Bayer, Boerhinger Ingelheim, Bristol Myers Squibb, EBR Systems, LivaNova, Medtronic, Novartis, and Windtree Therapeutics; and personal fees from Amgen, AstraZeneca, Cytokinetics, Merck & Co, and Servier Laboratories. All other authors report no relevant disclosures., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: Serial assessment of natriuretic peptides is widely utilized in heart failure clinics. Uncertainty exists regarding the value of multiple natriuretic peptide measurements and how they might be best interpreted., Methods and Results: Six hundred thirty-two patients with heart failure with reduced ejection fraction (<40%) and complete biomarker data were enrolled to receive sacubitril/valsartan. Patients underwent periodic study visits during 1-year follow-ups. Echocardiographic data and cardiac biomarkers, including N-terminal pro-B-type natriuretic peptide (NT-proBNP) were collected during study visits. Patients were categorized into three groups based on tertiles of baseline NT-proBNP levels. The area under the curve (AUC) of NT-proBNP measurements across study visits was calculated. Compared with patients with higher AUC (and thus higher concentrations over a longer period of time), those with lower AUC were younger, had a lower prevalence of chronic kidney disease, prior coronary artery bypass graft, atrial fibrillation, and higher body-mass index. A significant interaction existed between baseline NT-proBNP and subsequent AUC for predicting LVEF change across visits (P-value < 0.001): among those with lower baseline NT-proBNP, similar improvements in left ventricular (LV) volumes LV ejection fraction, and LV mass index were observed across subsequent AUC (P-value > 0.1). However, among those with higher baseline NT-proBNP, those with lower subsequent AUC had a greater improvement in cardiac remodelling indices (P-value < 0.05)., Conclusions: Serial NT-proBNP monitoring (integrating the totality of measurements as an AUC) during treatment with sacubitril/valsartan informs unique information regarding the future changes in cardiac remodelling indices, especially among those with higher NT-proBNP levels at baseline., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Background: Sacubitril/valsartan (S/V) treatment is associated with reverse cardiac remodeling and reductions in biomarkers reflecting ventricular wall stress and myocardial injury, such as NT-proBNP (N-terminal pro-B-type natriuretic peptide), hs-cTnT (high-sensitivity cardiac troponin T), and soluble suppressor of tumorigenicity 2 (sST2). How longitudinal changes in these biomarkers analyzed collectively are associated with cardiac remodeling in patients with heart failure with reduced ejection fraction treated with S/V is uncertain., Methods: In a prospective study of S/V in patients with heart failure with reduced ejection fraction, this prespecified exploratory analysis included patients with serially collected biomarkers and echocardiographic measures of cardiac remodeling through 12 months of treatment. A multivariate latent growth curve model assessed associations between simultaneous changes in biomarkers and left ventricular ejection fraction and left atrial volume index., Results: Seven hundred fifteen out of 794 total study participants were included (mean age 65 years, 73% male). Mean baseline left ventricular ejection fraction and left atrial volume index were 29% and 40 mL/m 2 , respectively. Adjusted geometric mean baseline concentrations for biomarkers included NT-proBNP of 649 pg/mL, hs-cTnT of 15.9 ng/L, and sST2 of 24.7 ng/mL. Following initiation of S/V, circulating concentrations of NT-proBNP, hs-cTnT, and sST2 significantly decreased within 30 days and remained significantly different than baseline at all subsequent timepoints. From baseline to month 12, decreases in adjusted biomarker concentrations averaged -27.9% (95% CI, -35.1% to -20.7%; P <0.001) for NT-proBNP; -6.7% (95% CI, -8.8% to -4.7%; P <0.001) for hs-cTnT; and -1.6% (95% CI, -2.9% to -0.4%; P <0.001) for sST2. NT-proBNP concentrations were predictive of later changes in hs-cTnT. The magnitude of reductions in NT-proBNP and hs-cTnT concentrations associated with improvements in left ventricular ejection fraction and left atrial volume index. There was no association between changes in sST2 and changes in other measures., Conclusions: Following initiation of S/V, NT-proBNP, hs-cTnT, and sST2 concentrations decreased significantly. Longitudinal changes in NT-proBNP and hs-cTnT together associated with left atrial and left ventricular reverse remodeling. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02887183.

Biomarkers have a well-defined role in the diagnosis and management of chronic heart failure, but their role in patients with left ventricular assist devices and cardiac transplant is uncertain. In this review, we summarize the available literature in this patient population, with a focus on clinical application. Some ubiquitous biomarkers, for example, natriuretic peptides and cardiac troponin, may assist in the diagnosis of left ventricular assist device complications and transplant rejection. Novel biomarkers focused on specific pathological processes, such as left ventricular assist device thrombosis and profiling of leukocyte activation, continue to be developed and show promise in altering the management of the advanced heart failure patient. Few biomarkers at this time have been assessed with sufficient scrutiny to warrant broad, universal application, but encouraging limited data and large potential for impact should prompt ongoing investigation.

Background The relationship between intensive volume removal in acute decompensated heart failure patients with preexisting worsening renal function (WRF) and renal tubular injury, postdischarge renal function, and clinical outcomes is unknown. Methods and Results We used data from the multicenter CARRESS-HF trial (Cardiorenal Rescue Study in Acute Decompensated Heart Failure) that randomized patients with acute decompensated heart failure and preexisting WRF to intensive volume removal with stepped pharmacological therapy or fixed rate ultrafiltration. Patients in the urinary renal tubular injury biomarker substudy (NAG [N-acetyl-b-D-glucosaminidase], KIM-1 [kidney injury molecule-1], and NGAL [neutrophil gelatinase-associated lipocalin]) were evaluated (N=105). The severity of prerandomization WRF was unrelated to baseline renal tubular injury biomarkers ( r=0.14; P=0.17). During randomized intensive volume removal, creatinine further worsened in 53% of patients. Despite a small to moderate magnitude increase in creatinine in most of these patients, postrandomization WRF was strongly associated with worsening in renal tubular injury biomarkers (odds ratio, 12.6; P=0.004). This observation did not differ by mode of volume removal (stepped pharmacological therapy versus ultrafiltration, P interaction =0.46). Increase in renal tubular injury biomarkers was associated with a higher incidence of hemoconcentration (odds ratio, 3.1; P=0.015), and paradoxically, better recovery of creatinine at 60 days ( P=0.01). Conclusions In acute decompensated heart failure patients with preexisting WRF, intensive volume removal resulted in a further worsening of creatinine approximately half of the time, a finding associated with a rise in tubular injury biomarkers. However, decongestion and renal function recovery at 60 days were superior in patients with increased tubular injury markers. These data suggest that the benefits of decongestion may outweigh any modest or transient increases in serum creatinine or tubular injury markers that occur during intensive volume removal. Clinical Trial Registration URL: https://www.clinicaltrials.gov . Unique identifier: NCT00608491.

Aims: We evaluated the added prognostic value of a multi-time point-based multimarker panel of biomarkers in patients with acute heart failure (AHF)., Methods and Results: Seven circulating biomarkers [NT-proBNP, high sensitivity cardiac troponin T (hs-cTnT), soluble ST2 (sST2), growth differentiation factor 15 (GDF-15), cystatin-C, galectin-3, and high sensitivity C-reactive protein (hs-CRP)] were measured at baseline and on days 2, 5, 14, and 60 in 1161 patients enrolled in the RELAX-AHF trial. Patients with BNP ≥350 ng/L or NT-proBNP ≥1400 ng/L, mild to moderate renal impairment, and systolic blood pressure >125 mmHg were included in the trial. Time-dependent Cox regression analysis was utilized to evaluate the incremental value of serial measurement of biomarkers. Added value of individual biomarkers and their combination, on top of a pre-specified baseline model, was quantified with the gain in the C-index. Serial biomarker evaluation showed incremental predictive value over baseline measurements alone for the prediction of 180-day cardiovascular mortality except for galectin-3. While a repeat measurement as early as day 2 was adequate for NT-proBNP and cystatin-C in terms of maximizing discriminatory accuracy, further measurements on days 14 and 60 provided added value for hs-cTnT, GDF-15, sST2, and hs-CRP. Individual biomarker additions on top of the baseline model showed additional prognostic value. The greatest prognostic gain was, however, attained with the combination of NT-proBNP, hs-cTnT, GDF-15, and sST2, which yielded 0.08 unit absolute increment in the C-index to 0.87 (95% confidence interval 0.83-0.91]., Conclusion: In patients with AHF and mild to moderate renal impairment, a multimarker approach based on a panel of serially evaluated biomarkers provides the greatest prognostic improvement unmatched by a single time point-based single marker strategy., (© 2017 The Authors. European Journal of Heart Failure © 2017 European Society of Cardiology.)

Objectives: The purpose of this study was to examine changes in a broad panel of biomarkers following left ventricular assist device (LVAD) support in advanced heart failure (HF)., Background: LVAD therapy mechanically unloads the failing heart and may result in reversal of certain aspects of the end-stage HF phenotype. Changes in markers of myocardial stress, fibrosis, inflammation, fluid homeostasis, and renal injury in this setting are unknown., Methods: Amino-terminal pro-B-type natriuretic peptide (NT-proBNP), galectin-3, ST2, copeptin, growth differentiation factor (GDF)-15, C-reactive protein (CRP), and neutrophil gelatinase associated lipocalin (NGAL) levels were measured in frozen plasma collected from 37 individuals prior to continuous flow LVAD implantation and a median of 136 (interquartile range: 94 to 180) days after implantation., Results: The median age of patients was 68 years old. LVAD therapy was associated with significant decreases in NT-proBNP (3,093 to 2,090 pg/ml; p = 0.02), ST2 (67.5 to 45.2 ng/ml, p <0.01), galectin-3 (24.7 to 22.0 ng/ml; p = 0.04), GDF-15 (3,232 to 2,613 ng/l;p <0.001), hs-CRP (22.4 to 11.9 mg/l; p = 0.01), and copeptin (103 to 94 pmol/l; p = 0.003) but not NGAL (132 to 135 ng/ml; p = 0.06). Despite improvement over time, absolute values of each biomarker remained extremely abnormal. Greater reductions in biomarkers were noted in individuals with >25% decrease in NT-proBNP concentrations but reached statistical significance only in the case of galectin-3 (p = 0.01)., Conclusions: The biomarker profile in patients after LVAD placement improves but nonetheless remains significantly abnormal. Our results suggest the need for targeted therapeutic interventions to mitigate such abnormalities and potentially increase rates of myocardial recovery., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Heart failure is a syndrome with a pathophysiological basis that can be traced to dysfunction in several interconnected molecular pathways. Identification of biomarkers of heart failure that allow measurement of the disease on a molecular level has resulted in enthusiasm for their use in prognostication and selection of appropriate therapies. However, despite considerable amounts of information available on numerous biomarkers, inconsistent research methodologies and lack of clinical correlations have made bench-to-bedside translations rare and left the literature with countless publications of varied quality. There is a need for a systematic and collaborative approach aimed at definitively studying the clinical benefits of novel biomarkers. In this review, on the basis of input from academia, industry, and governmental agencies, we propose a systematized approach based on adherence to specific quality measures for studies looking to augment current prediction model or use biomarkers to tailor therapeutics. We suggest that study quality, rather than results, should determine publication and propose a system for grading biomarker studies. We outline the need for collaboration between clinical investigators and statisticians to introduce more advanced statistical methodologies into the field of biomarkers that would allow for data from a large number of variables to be distilled into clinically actionable information. Lastly, we propose the creation of a heart failure biomarker consortium that would allow for a comprehensive list of biomarkers to be concomitantly analyzed in a pooled sample of randomized clinical trials and hypotheses to be generated for testing in biomarker-guided trials. Such a consortium could collaborate in sharing samples to identify biomarkers, undertake meta-analyses on completed trials, and spearhead clinical trials to test the clinical utility of new biomarkers., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Objectives: The aim of this study was to determine whether biomarkers of myocardial stress and fibrosis improve prediction of the mode of death in patients with chronic heart failure., Background: The 2 most common modes of death in patients with chronic heart failure are pump failure and sudden cardiac death. Prediction of the mode of death may facilitate treatment decisions. The relationship between amino-terminal pro-brain natriuretic peptide (NT-proBNP), galectin-3, and ST2, biomarkers that reflect different pathogenic pathways in heart failure (myocardial stress and fibrosis), and mode of death is unknown., Methods: HF-ACTION (Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training) was a randomized controlled trial of exercise training versus usual care in patients with chronic heart failure due to left ventricular systolic dysfunction (left ventricular ejection fraction ≤35%). An independent clinical events committee prospectively adjudicated mode of death. NT-proBNP, galectin-3, and ST2 levels were assessed at baseline in 813 subjects. Associations between biomarkers and mode of death were assessed using cause-specific Cox proportional hazards modeling, and interaction testing was used to measure differential associations between biomarkers and pump failure versus sudden cardiac death. Discrimination and risk reclassification metrics were used to assess the added value of galectin-3 and ST2 in predicting mode of death risk beyond a clinical model that included NT-proBNP., Results: After a median follow-up period of 2.5 years, there were 155 deaths: 49 from pump failure, 42 from sudden cardiac death, and 64 from other causes. Elevations in all biomarkers were associated with increased risk for both pump failure and sudden cardiac death in both adjusted and unadjusted analyses. In each case, increases in the biomarker had a stronger association with pump failure than sudden cardiac death, but this relationship was attenuated after adjustment for clinical risk factors. Clinical variables along with NT-proBNP levels were stronger predictors of pump failure (C statistic: 0.87) than sudden cardiac death (C statistic: 0.73). Addition of ST2 and galectin-3 led to improved net risk classification of 11% for sudden cardiac death, but not pump failure., Conclusions: Clinical predictors along with NT-proBNP levels were strong predictors of pump failure risk, with insignificant incremental contributions of ST2 and galectin-3. Predictability of sudden cardiac death risk was less robust and enhanced by information provided by novel biomarkers., (Copyright © 2014 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Background: Exercise training is recommended for chronic heart failure (HF) patients to improve functional status and reduce risk of adverse outcomes. Elevated plasma levels of amino-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cardiac troponin T (cTnT) are associated with increased risk of adverse outcomes in this patient population. Whether exercise training leads to improvements in biomarkers and how such improvements relate to clinical outcomes are unclear., Methods and Results: Amino-terminal pro-brain natriuretic peptide, hs-CRP, and cTnT levels were assessed at baseline and 3 months in a cohort of 928 subjects from the HF-ACTION study, a randomized clinical trial of exercise training versus usual care in chronic HF patients with reduced left ventricular ejection fraction (<35%). Linear and logistic regressions were used to assess 3-month biomarker levels as a function of baseline value, treatment assignment (exercise training vs usual care), and volume of exercise. Linear regression and Cox proportional hazard modeling were used to evaluate the relations between changes in biomarker levels and clinical outcomes of interest that included change in peak oxygen consumption (peak VO2), hospitalizations, and mortality. Exercise training was not associated with significant changes in levels of NT-proBNP (P = .10), hs-CRP (P = .80), or detectable cTnT levels (P = .83) at 3 months. Controlling for baseline biomarker levels or volume of exercise did not alter these findings. Decreases in plasma concentrations of NT-proBNP, but not hs-CRP or cTnT, were associated with increases in peak VO2 (P < .001) at 3 months and decreased risk of hospitalizations or mortality (P ≤ .04), even after adjustment for a comprehensive set of known predictors., Conclusions: Exercise training did not lead to meaningful changes in biomarkers of myocardial stress, inflammation, or necrosis in patients with chronic HF. Only improvements in NT-proBNP translated to reductions in peak VO2 and reduced risk of clinical events., (© 2014.)

Objectives: The aim of this study was to assess the effects of serelaxin on short-term changes in markers of organ damage and congestion and relate them to 180-day mortality in patients with acute heart failure., Background: Hospitalization for acute heart failure is associated with high post-discharge mortality, and this may be related to organ damage., Methods: The Pre-RELAX-AHF (Relaxin in Acute Heart Failure) phase II study and RELAX-AHF phase III study were international, multicenter, double-blind, placebo-controlled trials in which patients hospitalized for acute heart failure were randomized within 16 h to intravenous placebo or serelaxin. Each patient was followed daily to day 5 or discharge and at days 5, 14, and 60 after enrollment. Vital status was assessed through 180 days. In RELAX-AHF, laboratory evaluations were performed daily to day 5 and at day 14. Plasma levels of biomarkers were measured at baseline and days 2, 5, and 14. All-cause mortality was assessed as a safety endpoint in both studies., Results: Serelaxin reduced 180-day mortality, with similar effects in the phase II and phase III studies (combined studies: N = 1,395; hazard ratio: 0.62; 95% confidence interval: 0.43 to 0.88; p = 0.0076). In RELAX-AHF, changes in markers of cardiac (high-sensitivity cardiac troponin T), renal (creatinine and cystatin-C), and hepatic (aspartate transaminase and alanine transaminase) damage and of decongestion (N-terminal pro-brain natriuretic peptide) at day 2 and worsening heart failure during admission were associated with 180-day mortality. Serelaxin administration improved these markers, consistent with the prevention of organ damage and faster decongestion., Conclusions: Early administration of serelaxin was associated with a reduction of 180-day mortality, and this occurred with fewer signs of organ damage and more rapid relief of congestion during the first days after admission., (Copyright © 2013 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Understanding of chronic heart failure (HF) has progressed from a syndrome of disordered hemodynamics caused by alterations in the structure of the heart to one that involves intertwined molecular pathways in disarray. Accordingly, the assessment and treatment of patients with chronic HF has shifted from a focus on hemodynamics to modification of maladaptive molecular processes. Accumulating evidence shows that molecular biomarkers of disease could provide a unique window into the pathophysiology of chronic HF, potentially improving our ability to predict adverse outcomes, provide novel drug targets, and even help gauge therapeutic efficacy. The more 'traditional' biomarkers such as cardiac troponin, natriuretic peptides, and C-reactive protein have been studied in large cohorts of patients with chronic HF and have relatively established clinical applications. In this Review, we summarize the properties, clinical data, and potential applications of some emerging biomarkers that could uniquely indicate the level of biomechanical stretch, inflammation, ventricular remodeling, myocardial injury, and renal dysfunction that occurs in chronic HF. We will also discuss the potential role for these biomarkers within a multimarker-based strategy that could, in the future, lead to better care for these patients.

Despite the continued growth of heart failure as a major public health problem, the development of new therapies for heart failure has slowed and recent studies have been neutral, suggesting the need for a reappraisal of the clinical research enterprise. Surrogate end points, defined as measurements that are used as substitutes for the more clinically meaningful end points, can play a valuable role in clinical trials by accelerating the timeline for determining appropriate dosages, efficacy, and safety. Biomarkers, such as the natriuretic peptides, have many of the characteristics of valid surrogates but have not been sufficiently validated for widespread use. Ongoing research into the role of biomarkers as surrogates may lead to better clinical trial design and more efficient development of new therapies for heart failure., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Advances in genomics and proteomics promise to transform biomarker research, in which the major challenges will not be the discovery of new markers but rather the optimal selection and validation of a subgroup of clinically useful markers from the large pool of candidates. Critically, the value of new biomarkers panels will need to be assessed in the context of readily available clinical information in order to create more actionable knowledge rather than just greater complexity. Appropriate methodologies for the clinical and statistical evaluation of so called "multi-marker strategies" have not been systematically defined. Although specific criteria for the appropriate clinical and statistical evaluation of multi-marker strategies will vary based on the intended use (e.g., diagnosis vs. screening), the ultimate measure of success is the ability for a biomarker panel to both correct a meaningful portion of misclassification by standard methods (discrimination) and to improve quantification of absolute risk (calibration) in comparison to existing clinical information. Findings should be validated in an independent dataset of the representative patient population before a given multi-marker strategy can be considered for clinical use. Here, we define multi-marker strategies, summarize recent examples of biomarker combinations in heart failure, address key statistical and clinical issues, and discuss future directions for this rapidly evolving field.

The management of heart failure remains challenging despite many therapeutic advances. Rigorous clinical trial evidence supports administration of multiple therapies, but utilization of evidence-based treatment remains inconsistent and suboptimal. Disease management programs appear effective, but remain costly and difficult to implement in today's care system. Another approach involves optimizing therapy based on serial monitoring of cardiac biomarkers. Emerging results suggest that guiding therapy based on serial changes in natriuretic peptides may be an effective strategy. Although pilot work has provided encouraging results, appropriately designed, large-scale, prospective randomized trials are needed to confirm these preliminary findings and definitively establish this therapeutic approach.

Background: Adverse outcomes have recently been linked to elevated red cell distribution width (RDW) in heart failure. Our study sought to validate the prognostic value of RDW in heart failure and to explore the potential mechanisms underlying this association., Methods and Results: Data from the Study of Anemia in a Heart Failure Population (STAMINA-HFP) registry, a prospective, multicenter cohort of ambulatory patients with heart failure supported multivariable modeling to assess relationships between RDW and outcomes. The association between RDW and iron metabolism, inflammation, and neurohormonal activation was studied in a separate cohort of heart failure patients from the United Investigators to Evaluate Heart Failure (UNITE-HF) Biomarker registry. RDW was independently predictive of outcome (for each 1% increase in RDW, hazard ratio for mortality 1.06, 95% CI 1.01-1.12; hazard ratio for hospitalization or mortality 1.06; 95% CI 1.02-1.10) after adjustment for other covariates. Increasing RDW correlated with decreasing hemoglobin, increasing interleukin-6, and impaired iron mobilization., Conclusions: Our results confirm previous observations that RDW is a strong, independent predictor of adverse outcome in chronic heart failure and suggest elevated RDW may indicate inflammatory stress and impaired iron mobilization. These findings encourage further research into the relationship between heart failure and the hematologic system., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Multiple lines of evidence support the "cytokine hypothesis," which suggests that inflammation plays an important role in the development and progression of heart failure. Circulating markers of inflammation, such as tumor necrosis factor alpha, interleukin 6, and C-reactive protein, may be useful in establishing the diagnosis, gauging prognosis, and evaluating the response to therapy in patients with heart failure. In addition to their potential as heart failure biomarkers, inflammatory cytokines have been investigated as targets of heart failure therapy. Although results for therapies directed against specific cytokines (such as tumor necrosis factor alpha) have thus far been disappointing, multiple studies continue to address the therapeutic potential of modulating the immune response in heart failure. In this review, the authors analyze available data supporting the use of inflammatory markers both as biomarkers and as potential therapeutic targets.

The natriuretic peptides are a family of related hormones that play a crucial role in cardiovascular homeostasis. They have recently emerged as potentially important clinical markers in heart failure. Recent data have suggested an important role for these markers in establishing the diagnosis of heart failure in patients with unexplained dyspnea in both acute care and ambulatory settings. Other clinical uses of the natriuretic peptides, such as screening for asymptomatic ventricular dysfunction, establishing prognosis or guiding titration of drug therapy, are under investigation but have not yet sufficiently been validated for widespread clinical use.

BackgroundAtrial fibrillation (AFib) is a common comorbidity in HF and affects patients' outcome. We sought to assess the effects of serelaxin in patients with and without AFib.MethodsIn a post hoc analysis of the RELAX-AHF trial, we compared the effects of serelaxin on efficacy end points, safety end points and biomarkers in 1161 patients with and without AFib on admission electrocardiogram.ResultsAFib was present in 41.3% of patients. Serelaxin had a similar effect in patients with and without AFib, including dyspnea relief by visual analog scale through day 5 [mean change in area under the curve, 541.11 (33.79, 1048.44), p = 0.0366 in AFib versus 361.80 (-63.30, 786.90), p = 0.0953 in non-AFib, interaction p = 0.5954] and all-cause death through day 180 [HR = 0.42 (0.23, 0.77), p = 0.0051 in AFib versus 0.90 (0.53, 1.52), p = 0.6888 in non-AFib, interaction p = 0.0643]. Serelaxin was similarly safe in the two groups and induced similar reductions in biomarkers of cardiac, renal and hepatic damage. Stroke occurred more frequently in AFib patients (2.8 vs. 0.8%, p = 0.0116) and there was a trend for lower stroke incidence in the serelaxin arm in AFib patients (odds ratios, 0.31, p = 0.0759 versus 3.88, p = 0.2255 in non-AFib, interaction p = 0.0518).ConclusionsSerelaxin was similarly safe and efficacious in improving short- and long-term outcomes and inducing organ protection in acute HF patients with and without AFib.

Heart failure (HF) afflicts nearly 6 million Americans, resulting in 1 million emergency department (ED) visits and over 1 million annual hospital discharges. The majority of inpatient admissions originate in the ED; thus, it is crucial that emergency physicians and other providers involved in early management understand the latest developments in diagnostic testing, therapeutics, and alternatives to hospitalization. This article discusses contemporary ED management as well as the necessary next steps for ED-based acute HF research.

Aims: We sought to determine sex‐based differences in biomarkers, self‐reported health status, and magnitude of longitudinal changes in measures of reverse cardiac remodelling among patients with heart failure with reduced ejection fraction (HFrEF, left ventricular ejection fraction ≤40%) treated with sacubitril/valsartan (S/V). Methods and results: This was a subgroup analysis of patients initiated on S/V in the Prospective Study of Biomarkers, Symptom Improvement and Ventricular Remodeling During Entresto Therapy for Heart Failure (PROVE‐HF) study. There were 226 (28.5%) women in the study. Though women had lower baseline N‐terminal pro B‐type natriuretic peptide (NT‐proBNP), they had more rapid early reduction in the biomarker after initiation of S/V. Compared to men, women had lower average baseline Kansas City Cardiomyopathy Questionnaire (KCCQ)‐23 Total Symptom score (67.6 vs. 71.9; P = 0.003) but showed greater linear improvement (7.4 vs. 5.5 points; P < 0.001) and faster pace of KCCQ change (P < 0.001) over the course of the trial. Women and men demonstrated similar degrees of reverse left ventricular remodelling following S/V initiation; however, women did so earlier than men with more consistent changes. These results remained unchanged with adjustment for relevant covariates. Reduction in NT‐proBNP was associated with reverse cardiac remodelling in both women and men. Treatment with S/V was well tolerated in all. Conclusions: In women with HFrEF, treatment with S/V was associated with significant NT‐proBNP reduction, health status improvement and reverse cardiac remodelling. [ABSTRACT FROM AUTHOR]