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Biomarkers in Heart Failure
How I Integrate Biomarkers Into the Management of Heart Failure

Released: October 10, 2016

Expiration: October 09, 2017

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The term “biomarker” refers to a range of objectively measured characteristics that can be evaluated as indicators of normal biological processes, pathogenic processes, or responses to a therapeutic intervention. Among patients with heart failure, biomarkers are typically used either to confirm a suspected clinical diagnosis or to refine the prognostic assessment.

Although the diagnosis of heart failure is classically made clinically based on the presence of typical symptoms (shortness of breath or fatigue on exertion, orthopnea, peripheral edema) and signs (rales on pulmonary exam, S3 gallop, elevated jugular venous pressure, hepatomegaly), definitive diagnosis may be challenging in some patients due to comorbidity, body habitus, or atypical presentations. Moreover, since there is varying expertise in the community of clinicians caring for patients with heart failure, not all have the same level of comfort or experience in making the heart failure diagnosis.

Among those in whom the heart failure diagnosis is well established, there is a need to assess the clinical response to therapy, monitor disease progression, and estimate prognosis to guide appropriate triage of patients for specialized interventions.

Using Biomarkers for Diagnosis
Biomarkers are most commonly employed to help confirm that heart failure is present when a patient presents with symptoms that could be related to a number of conditions, including heart failure. Among patients with undifferentiated dyspnea presenting to the emergency department, elevated levels of the natriuretic peptides, B-type natriuretic peptide (BNP) or its cousin, N-terminal proBNP (NT-proBNP), increase the likelihood that heart failure is present as a contributing factor. These natriuretic peptides are released into the serum by the ventricular myocardium in response to increased wall stress and are accordingly elevated in patients with volume overload or congestion. An elevated BNP level does not guarantee that heart failure is present, but the greater the degree of elevation, the more likely that heart failure is a factor in explaining the patient’s symptoms. In general, use of the natriuretic peptides is most helpful in influencing a clinician to include the heart failure diagnosis when there is clinical uncertainty.

So how high does BNP need to be? Evidence-based thresholds are used for heart failure diagnosis. For BNP, the original studies by Alan Maisel and colleagues in the Breathing Not Properly Multinational Study suggested that patients presenting to the emergency department with undifferentiated dyspnea who had a BNP level in excess of 100 pg/mL were very likely to have dyspnea due to heart failure, with a positive predictive value of approximately 80%. Use of higher cutpoints to define the heart failure diagnosis enhances the specificity of the test, particularly in subjects not previously known to have heart failure. NT-proBNP levels have similar value if the appropriate cutpoints are chosen in relation to patient age. Of equal importance, a BNP level < 100 pg/mL or an NT-proBNP level < 300 pg/mL can help to rule out acute heart failure in 9 out of 10 cases.

There are several factors that can confound the measure of BNP and NT-proBNP, including chronic kidney disease or renal failure, hypertension, pulmonary embolism, valvular heart disease, and even patient factors such as obesity. Obese patients tend to have lower BNP levels than thin patients with the same severity of heart failure, and similarly, patients with heart failure and preserved ejection fraction tend to have lower BNP levels even for the same degree of congestion that patients with heart failure and reduced ejection fraction have. Accordingly, natriuretic peptide levels must be integrated into the overall clinical assessment when used to facilitate heart failure diagnosis.

Using Biomarkers for Prognosis
Regarding prognosis in heart failure, numerous different biomarkers have been explored. Several physical exam signs are correlated with prognosis in patients with heart failure, including jugular venous pressure and heart rate.  In addition, serum laboratory measures, such as serum sodium, blood urea nitrogen, serum creatinine, and the estimated glomerular filtration rate, can be leveraged in tandem with clinical factors to enhance the assessment of prognosis in patients with heart failure. Cardiac biomarkers including the natriuretic peptides and cardiac troponins are potent correlates of prognosis in heart failure, both in the hospitalized setting and in the ambulatory setting. Among patients hospitalized with heart failure, for example, the predischarge level of BNP correlates very strongly with the risk for rehospitalization and death from heart failure complications, and it may help to triage patients at high risk for specialized follow-up or other advanced interventions. Various other cardiac biomarkers are under investigation to help refine the prognostic assessment but are not yet routinely employed in clinical practice.

Use of Biomarkers to Guide Therapy
An increasingly interesting application of biomarkers is to help assess the response to treatment and guide optimization of the medical regimen. In this regard, heart rate has emerged as a potent correlate of prognosis, particularly in patients with heart failure and reduced ejection fraction, and may be used to help optimize dosing of β-blockers and select patients for novel therapies such as ivabradine. In addition, serial measurement of natriuretic peptides may help to identify patients who are candidates for intensification of heart failure therapy. Small randomized trials conducted to date have shown mixed results as to whether this approach improves hard clinical outcomes in heart failure. However, the GUIDE-IT trial is an ongoing prospective, randomized trial of heart failure management guided by serial measurement of natriuretic peptide levels (targeting adjustment of therapy to achieve and maintain an NT-proBNP level < 1000 pg/mL vs adjustment of therapy based on clinical signs alone) and should provide definitive data about whether this approach should be employed routinely in clinical practice.

Summary of My Approach
In my practice, I tend to use biomarkers in multiple ways. In longitudinal heart failure management, I use serial measurement of body weights (which could be considered a biomarker) as a surrogate measure of congestion to help guide diuretic titration and provide a tool for patients to self-monitor their disease.  In patients with heart failure and reduced ejection fraction, I use heart rate as a measure of the adequacy of β-blocker treatment and to help select patients for treatment with ivabradine. I measure serum levels of natriuretic peptides when I am uncertain about the diagnosis of heart failure to influence my overall clinical assessment of the patient. Furthermore, I measure natriuretic peptides in patients as they leave the hospital or in patients in whom I’m concerned of worsening symptoms to help prognosticate and influence my decision making about how aggressive to be with employing advanced therapies or considering more intensive heart failure intervention. I have not yet taken to routine measurement of natriuretic peptide levels in longitudinal management of ambulatory patients with heart failure but am eager to see if the GUIDE-IT trial will alter my practice by demonstrating the benefits of this approach vs usual guideline-based clinical management.

Your Thoughts
How do you use biomarkers when managing patients with heart failure? Answer the polling question and leave your thoughts in the comments section below. For more discussion of diagnosis, treatment, and new therapeutic options for heart failure, don’t miss this CME-certified video featuring Keith C. Ferdinand, MD, FACC, FAHA.

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Poll

1.
A 52-year-old man with long-standing hypertension, chronic obstructive pulmonary disease, obstructive sleep apnea, and obesity presents with increasing fatigue and shortness of breath. His breathing at night is also labored but aided by being propped up on 3 pillows. His only medications are hydrochlorothiazide 25 mg/day and atenolol 50 mg/day.

On examination, his pulse is 104 beats/minute and blood pressure is 134/84 mm Hg. The jugular venous pressure is challenging to assess. The lung exam shows diffuse expiratory wheezing. The heart sounds are distant, but no clear gallop is audible. There is 2+ pedal edema.

Which of the following diagnostic tests would be most useful in helping to assess a contribution of heart failure to this patient’s symptoms?
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