The following are points to remember about this American Heart Association (AHA) Scientific Statement on the role of biomarkers for prevention, assessment, and management of heart failure (HF):

1. Pathophysiology of HF:
   • Neurohormones: Elevated levels of neurohormones in blood occur even in patients with asymptomatic left ventricular (LV) dysfunction, and when symptoms of HF appear, they rise according to severity. Despite a strong association between neurohormone levels in the blood and the clinical course of patients with HF, complex assays and handling procedures required for processing neurohormones such as norepinephrine and epinephrine make clinical use impractical.
   • Markers of Extracellular Matrix Remodeling: Increased levels of matrix metalloproteinases (MMPs) or tissue inhibitors of matrix metalloproteinases (TIMPs) and the ratio between them have been associated with disease status, and it has been postulated that profiling these molecules will provide prognostic information.
   • Inflammatory Mediators and Markers of Oxidative Stress:
     • Toll-like receptor molecule: The increased spillover into the circulation of toll-like receptor molecules makes them potentially useful as biomarkers that can be used to assess risk and to provide important insights into the mechanisms involved in the pathogenesis of HF.
     • Cytokines: The mediators that have proved most useful as biomarkers in HF include the proinflammatory cytokines tumor necrosis factor-alpha, interleukin (IL)-1, IL-6, growth differentiation factor 15 (GDF-15), and C-reactive protein (CRP).
     • Suppressor of tumorgenicity 2 (ST2) concentrations are elevated in HF.
     • Galectin-3 (gal-3), a β-galactoside–binding lectin member of the galectin family, is another biomarker of inflammatory response in HF.
   • Myocyte Injury and Stress:
     • Release of myofibrillar proteins such as troponin T (TnT) and troponin I (TnI) occurs in HF in the absence of an acute coronary event.
     • BNP and its amino terminal NT-BNP are released into circulation directly from the myocardium as a result of end-diastolic stress as results of increases in volume or pressure.
   • Other Biomarkers: MicroRNAs are short, noncoding RNA sequences that regulate gene expression at the posttranscriptional level by targeting the 3’-untranslated region of mRNA sequences.
2. Assessing Risk of Incident HF:
   • BNP and NT-proBNP have the best predictive value and are stronger than ANP or NT-proANP. Also, physical activity decreases the likelihood for an increase in NT-proBNP and hs-troponin over time, and this was associated with a lower risk of new-onset HF. Elevated troponin concentrations generally have a stronger relation with future risk of HF than ischemic events. In community-based populations, measurement of natriuretic peptides (BNP or NT-proBNP) or markers of myocardial injury (TnI or TnT) alone adds prognostic information to standard risk factors for predicting new-onset HF.
   • Renal dysfunction as reflected by creatinine or cystatin-C is a strong predictor of new-onset HF. Gal-3, sST2, and GDF-15 collectively have shown to have additive prognostic value in risk models for new-onset HF. Therefore, measurement of several new biomarkers, including sST2, Gal-3, GDF-15, and markers of renal function, alone or in a multimarker strategy, may be useful for providing additional risk stratification.
3. Biomarkers for Diagnosis of HF:
   • BNP accurately diagnoses HF in patients presenting to the emergency department with shortness of breath, with a sensitivity of 90% and specificity of 76% at a cut-off value of 100 pg/ml; the proposed rule-in cutoff is >400 pg/ml. For NT-proBNP to improve, positive predictive value age-related cut-offs of 450 pg/ml for <50 years, 900 pg/ml for 50-75 years, and 1800 pg/ml for >75 years are recommended. Cautious interpretation of concentrations is important in the presence of confounders such as age; obesity; and cardiac, pulmonary, and renal disease. Measurement of BNP and NT-proBNP is useful in the setting of uncertainty to support the clinical diagnosis of acute decompensated or ambulatory HF.
   • Circulating levels of natriuretic peptides are elevated in HF with preserved ejection fraction (HFpEF), but are lower in concentrations than in patients with HFrEF. To support the diagnosis of HFpEF, partition values for diagnosis are a BNP ≥100 pg/ml and NT-proBNP ≥800 pg/ml.
   • Changes in microRNA 29a, 1, 21, and 133a are associated with myocardial fibrosis in patients with HFpEF, but these have not been applied as diagnostic or prognostic biomarkers in such patients.
4. Biomarkers for Prognosis of Chronic HF:
   • Elevated BNP or NT-proBNP parallel HF disease severity, assessment of New York Heart Association (NYHA) class, elevated filling pressures, or worse hemodynamics are suggestive of worse clinical outcomes and mortality in HF. Each increase in BNP by 100 pg/ml is associated with a 35% increase in relative risk of mortality (95% confidence interval [CI], 22-49; p = 0.096). Detectable levels of hs-Tn level predict worse outcomes including mortality (hazard ratio, 2.08; 95% CI, 1.72-2.52) at 2 years.
   • Serum ST2 does not improve the ability to discriminate patients in a multivariable model, but it did increase the sensitivity of 1-year outcome predictions. More studies are required to determine the utility and prognostic value of midregional proadrenomedullin (MR-proADM) and galectin-3.
5. Biomarkers for Prognosis of Acute HF:
   • In patients with acutely decompensated HF, measurement of BNP or NT-proBNP and cardiac Tn at the time of presentation is useful for establishing prognosis or disease severity.
   • Predischarge BNP and NT-pro-BNP are stronger markers of post-discharge outcomes than either baseline or percent change in BNP during hospitalization.
6. Outpatient Management of HF:
   • Biomarker–guided, with either BNP- or NT-proBNP, HF therapy is of uncertain benefit in clinical practice and therefore not advised.
   • The utility of serial measurement of BNP or NT-proBNP to reduce HF hospitalization or mortality is not well established.
   • Until prospectively acquired randomized data are available, the response of NT-proBNP to neprilysin inhibition with concomitant renin-angiotensin-aldosterone system inhibition is associated with positive clinical outcomes, but should not be used as a surrogate to guide treatment with an angiotensin-receptor/neprilysin inhibitor compound.
7. Management of HF Hospitalization:
   • The utility of BNP- or NT-proBNP–guided therapy for acutely decompensated HF is not well established.
   • In hospitalized patients with acutely decompensated HF, BNP or NT-proBNP concentrations collected after treatment may be useful for prognosis.
8. Biomarkers in Clinical Trials and Quality Assurance Programs:
   • Measurement of biomarkers may be useful, in clinical trials of HF, as a component of study entry criteria, in establishing disease severity, and in better identifying an at-risk population to be enrolled.
   • Biomarkers may be useful in clinical trials for providing mechanistic insights, identifying cohorts of patients with greater or lesser therapeutic responses or safety risks, or targeting certain mechanisms of action.
   • In quality assurance programs, biomarkers may be helpful for identifying patients with or at risk for HF, establishing disease severity, and stratifying risk.
   • In phase III randomized clinical trials, the use of biomarkers, as primary endpoints as surrogates for clinical outcomes, is not well established.
9. Genomic Markers:
   • The routine utilization of metabolic or genotypic profiles for diagnosis, screening, or risk stratification of HF patients is not yet well established.
10. Global Perspective for Biomarker Application:
    • As the global pandemic of HF burden is to continue to increase, it is important to develop economical methods for biomarker measurement so that it can be utilized worldwide.

Keywords: Atrial Natriuretic Factor, Cardiac Surgical Procedures, C-Reactive Protein, Creatinine, Cystatin C, Cytokines, Dyspnea, Emergency Service, Hospital, Exercise, Extracellular Matrix, Galectin 3, Genomics, Geriatrics, Growth Differentiation Factor 15, Heart Failure, Inflammation Mediators, Interleukin-1 Receptor Accessory Protein, Interleukin-6, Matrix Metalloproteinases, Myocardium, Natriuretic Peptide, Brain, Neprilysin, Neurotransmitter Agents, Norepinephrine, Obesity, Oxidative Stress, Peptide Fragments, Primary Prevention, Risk Factors, Troponin I, Troponin T, Tumor Necrosis Factor-alpha

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