Biomarkers: Their potential in the diagnosis and treatment of heart failure

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ABSTRACTThe increasing use of cardiac biomarkers in the diagnosis and management of heart failure (HF) has led to their inclusion in clinical practice guidelines. Studies have demonstrated that natriuretic peptides and cardiac troponins are useful adjuncts in identifying patients with HF at high risk, and we now know that a number of factors influence biomarker levels, including age, renal failure, obesity, and comorbid conditions, and that these factors as well as biomarker assay variability need to be considered when interpreting the results of biomarker testing. The broader use of cardiac biomarker testing has been limited by the lack of consistent data to support a benefit of their use in triaging management decisions, and the majority of drug therapies and titration schedules for HF were developed prior to the availability of biomarkers. Nevertheless, natriuretic peptide testing has been widely adopted, with recent guidelines supporting its use in the diagnosis of acute HF, especially in the setting of clinical uncertainty, as well as in assessing disease severity and prognosis. This review summarizes the data on traditional cardiac biomarkers and describes how the latest investigations have shaped the recommendations in the latest clinical practice guidelines.


  • The usefulness of a biomarker may differ from one patient population to another, from one clinician to another, or from one clinical scenario to another.
  • For risk stratification in heart failure (HF), biomarkers that reflect renal insufficiency are especially powerful prognosticators.
  • In the latest clinical guidelines, natriuretic peptide testing has gained the highest level of recommendation for clinical use for any biomarker in HF.
  • In general, point-of-care assays are often more variable than the same tests done in clinical laboratories; sample collection, handling, and processing also introduce variability.



The growth in recognition and clinical adoption of blood and urine biomarkers over the last 20 years has been a major advance in the diagnosis and prognosis of heart failure (HF). While there have been numerous research studies and prospective clinical trials on this topic, healthcare providers often face limited availability of biomarker testing and a relative paucity of data to guide individual patient management. This is especially true since many guideline-directed medical therapies have long-established clinical indications and target populations, predating the clinical availability of biomarkers testing. This article addresses the salient insights gained from broad clinical use of biomarkers, as well as from clinical studies that helped define their appropriate use and lay the foundations of the major changes presented in the recently published clinical guidelines for the management of HF.


To appreciate the appropriate use of any clinical tool, clinicians need to first understand its indications and limitations and how they are defined. There are four major criteria regarding the clinical utility of a biomarker.

First, we have to establish what we are measuring, particularly with accurate and reproducible methods, with rapid turnaround, and at a reasonable cost. Second, we have to determine why we need the biomarker: ie, we need to determine if its measurement provides valuable new information to the clinician, if there is a strong and consistent association between the marker and the disease or outcome, and if this has been validated in a way that is generalizable. Third, we have to determine when measuring the biomarker would help clinical management, whether it is superior to existing tests, and whether there is evidence that it improves outcomes. Last, and perhaps most commonly overlooked, is practicality: ie, how can measuring the biomarkers be incorporated into the clinical workflow?

Not all biomarkers need to fulfill all these criteria in order to be useful, and the usefulness of a biomarker may differ from one patient population to another, from one clinician to another, or from one clinical scenario to another.1 Many clinical biomarkers are applied based on their ability to indicate a specific diagnosis or treatment (eg, glycated hemoglobin), and some have been used to determine the limits of therapy (eg, creatinine or liver function tests to detect end-organ damage). Nevertheless, the overarching goal is to establish the clinical role of a biomarker to provide the opportunity to gain additional insight into a disease state beyond that provided by a standard clinical assessment, and to determine if using the biomarker favorably alters the clinical course.


Traditionally, the management of HF requires meticulous monitoring for adverse effects of drug therapy (eg, electrolyte and renal abnormalities with diuretics or drugs targeting the renin-angiotensin-aldosterone system). Although no specific clinical studies have been conducted to support their routine use, electrolytes (sodium, potassium, chloride, bicarbonate) and renal function measurements (blood urea nitrogen [BUN], creatinine) are often repeated periodically in the longitudinal care of patients with HF.2 Diagnostic tests for hemochromatosis, human immunodeficiency virus, rheumatologic disease, amyloidosis, and pheochromocytoma are reasonable in patients presenting with HF in whom there is a clinical suspicion of these diseases.2

For risk stratification, biomarkers that reflect renal insufficiency (particularly sodium, BUN, creatinine, and the estimated glomerular filtration rate [eGFR]) are powerful prognosticators.3 Newer renal markers of glomerular function (such as cystatin C)4,5 or of acute kidney injury (such as neutrophil gelatinase-associated lipocalin)6,7 have been proposed, although their clinical utility beyond prognostication remains to be determined. In fact, head- to-head comparisons have revealed that BUN appeared to be superior to most other renal biomarkers in stratifying short-term and long-term risk.8

Liver function, blood cell count, and thyroid function profiles are checked on some occasions to determine underlying end-organ dysfunction.2 Interestingly, several common laboratory values have consistently been associated with more advanced disease states or with a higher risk of future adverse events. These include serum uric acid (likely reflecting oxidative stress and nucleotide catabolism),9 anemia or red cell distribution width (likely reflecting iron deficiency or hematopoietic insufficiency),10 lymphocytopenia (likely reflecting immune dysfunction), and total bilirubin (likely reflection of hepatobiliary congestion).11

Some biomarkers have been incorporated into risk-stratification in patients with HF.2 However, drugs targeting these biomarkers have yet to be shown to improve clinical outcomes in prospective clinical trials. Several recent examples in chronic systolic HF include allopurinol for elevated uric acid levels12 and darbepoetin alfa for anemia (low hemoglobin).13 Thus, improving the biomarker level with specific treatment may not translate to improved clinical outcomes.

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