Although BNP was first isolated by Sudoh et al. in 1988, its role as a biomarker in acute heart failure was not established until 2002. The multicenter Breathing Not Properly trial, by Maisel et al., was the first study to validate the effectiveness of BNP in the diagnostic workup of patients presenting to the emergency department (ED) with acute dyspnea. In this study, a BNP > 100 pg/mL was shown to be 73 % specific and 90 % sensitive for the diagnosis of acute heart failure with a diagnostic accuracy of 83.4 %. The negative predictive value of BNP < 50 pg/mL for acute heart failure was 96 % [2]. Besides BNP, NT-proBNP has also been studied extensively for the diagnostic evaluation of patients with acute dyspnea. In the PRIDE (Pro-Brain Natriuretic Peptide Investigation of Dyspnea in the Emergency Department) study by Januzzi et al., NT-proBNP was shown to have comparable sensitivity and slightly higher specificity (90 % sensitive and 85 % specificity) for the diagnosis of acute heart failure [3]. Natriuretic peptide levels are highly reproducible and can be checked with ease in a typical clinical laboratory. Adding natriuretic peptide levels to the standard diagnostic evaluation of acutely dyspneic patients can significantly reduce clinical indecision and diagnostic lag time, leading to their widespread acceptance (Fig. 12.1). ANP, although discovered around the same time as BNP, suffers from in vitro instability, which has limited its use in routine clinical practice. Recently, biochemical assays targeting a stable fragment of the ANP prohormone, mid-region proANP (MR-proANP), became available, leading to the emergence of ANP as a diagnostic in acute heart failure. The diagnostic utility of MR-proANP was examined in a large-scale multinational study, Biomarker in Acute Heart Failure (BACH) trial by Maisel et al. in 2008. In the BACH trial, 1641 patients with acute dyspnea were studied for the diagnostic accuracy of MR-proANP for acute heart failure. This study demonstrated that MR-proANP ≥ 120 pmol/L was non-inferior to BNP > 100 pg/L for the diagnosis of acute heart failure (Table 12.2). Requiring both BNP and MR-proANP to be elevated increased the diagnostic accuracy of acute heart failure to 76.6 % compared to 73.6 % for BNP elevation alone. In addition, MR-proANP measurements added to the diagnostic accuracy of BNP in patients with intermediate BNP value and obesity, but not in renal insufficiency, elderly patients, and patients with edema [4].

Another important function of natriuretic peptides is their use in the risk stratification of heart failure patients. The ability to accurately risk stratify patients can allow clinicians to tailor therapy to fit each patient’s needs. These individualized treatments will not only decrease morbidity and mortality but also reduce cost to the overall health system. Both BNP and NT-proBNP have been studied with promising results in the prognostic evaluation of heart failure patients.

Multiple natriuretic peptide studies have been performed in the ED setting, mostly in patients presenting with acute dyspnea. While the majority of these studies focused on the diagnostic utility of natriuretic peptides, major prognostic evidence had arisen as well. For example, the ADHERE (Acute Decompensated Heart Failure National Registry) database of 65,275 acute heart failure patients showed that BNP level at the time of admission had a nearly linear relationship with the risk for in-hospital mortality. The adjusted odds ratio for mortality between BNP quartile 4 (BNP > 1730 pg/mL) and BNP quartile 1 (BNP < 430 pg/mL) was 2.23 with p < 0.0001. In addition, initial ED BNP levels can identify patients at high risk for 30-day mortality or readmission [5]. These findings were confirmed and expanded upon later in an analysis of the Get With The Guidelines Heart Failure registry. In this study, the admission BNP of 99,930 acute heart failure patients was analyzed by gender and categories of ejection fraction including reduced (<40 %), borderline (40–49 %), and preserved (≥50 %). Though there were differences in BNP values between genders and ejection fraction categories, in all categories and genders, patients with a BNP above the median had higher mortality than those below. BNP remained predictive of in-hospital mortality after adjusting for over 20 variables [6]. These two large registry studies highlight BNP’s prognostic ability for mortality.

NT-proBNP is also highly prognostic in patients with acute heart failure. Januzzi et al. demonstrated that an ED NT-proBNP level greater than 1000 pg/mL is indicative of severe heart failure and is associated with adverse prognosis [7]. Furthermore, the IMPROVE-CHF (Canadian Multicenter Improved Management of Patients with Congestive Heart Failure) study showed that knowing a patient’s NT-proBNP level during ED evaluation can decrease the duration of the ED visit by 21 % and reduce 60-day rehospitalization rate by 35 % in addition to reducing overall medical costs [8].

The prognostic value of natriuretic peptides can play an important role in guiding treatment strategies. Having a baseline natriuretic peptide level when a patient’s heart failure is stable can go a long way to assist with prognostic evaluation when he/she goes into acute heart failure. Acute heart failure patients whose natriuretic peptide levels remain elevated despite appropriate inpatient therapy often have a poorer prognosis and require closer follow-up in the outpatient setting. For example, Bettencourt et al. showed that among 182 patients admitted to the hospital for acute heart failure, discharge NT-proBNP above the median (>4137 pg/mL) was associated with increased post-discharge adverse outcomes. He also showed that the change in NT-proBNP values with treatment is highly prognostic. Patients with NT-proBNP increase greater than 30 % from admission to discharge had the worse outcome, followed by patients with less than 30 % change in NT-proBNP levels. Patients with more than a 30 % decrease in NT-proBNP levels had the best outcome. The single best predictor of mortality and readmission in this study was the change in NT-proBNP levels from admission to discharge [9]. Within the hospital setting, the current general consensus is to obtain a natriuretic peptide value at admission and again prior to discharge when the patient is deemed to be clinically optivolemic. Repeat natriuretic peptide levels are suggested if there is clinical deterioration. While some trials have shown that the lower the natriuretic peptide level at discharge, the lower the risk of death and readmission, overall, the literature has been inconsistent. Still, an as-low-as-possible natriuretic peptide level is a reasonable goal for clinicians to aim for while treating a patient for acute heart failure. In fact, a BNP level of <350 pg/mL or NT-proBNP level <4000 pg/mL at discharge is generally linked to a stable post-hospital course, which is especially true if the patient is clinically optivolemic.

As to why a patient’s natriuretic peptide level can remain elevated despite recommended in-hospital treatment, the answer may be multifactorial. First, the high natriuretic peptide level could reflect the severity of patient’s baseline heart failure, which may result in persistently elevated ventricular wall stress. Second, excessive treatment with diuretics may cause the patient to enter a prerenal state leading to a decreased GFR. Because natriuretic peptides are partly cleared by the kidneys, a decreased GFR can lead to inappropriately elevated natriuretic peptide levels due to poor clearance. In patients with concurrent right heart failure leading to edema and ascites, significant diuresis can occur prior to any effects on ventricular preload, resulting in persistent elevation of ventricular wall stress despite diuresis. Finally, there is the possibility that the treatment was inadequate and ventricular wall stress remains elevated despite treatment [3].

Perhaps the most exciting and rapidly expanding use of natriuretic peptides is in the outpatient setting, where natriuretic peptides can help to identify patients who are at high risk for future adverse events. For example, the Framingham Offspring Study, which evaluated 3346 asymptomatic outpatients, demonstrated that elevated natriuretic peptide levels were predictive of future adverse cardiovascular events and mortality. In this particular cohort, BNP values above the 80th percentile were associated with increased risk for death (hazard ratio = 1.62, p = 0.02), first major cardiovascular event (hazard ratio = 1.76, p = 0.03), atrial fibrillation (hazard ratio = 1.91, p = 0.02), stroke or transient ischemic attack (hazard ratio = 1.99, p = 0.02), and heart failure (hazard ratio = 3.07, p = 0.002) [10]. These natriuretic peptide elevations in asymptomatic patients may reflect a change in cardiac or renal function that has not yet manifested as clinical deterioration. Measuring natriuretic peptides in these patients can help to identify clinical deteriorations early on and assist with therapeutic interventions to prevent the development of significant symptoms.

In outpatient management of heart failure, it is very important to know each patient’s optivolemic natriuretic peptide level, which can serve as a baseline for comparison during subsequent evaluations. This is especially true in cases where symptoms have not yet appeared. A greater than 50 % rise of natriuretic peptide levels from baseline is associated with high risk for impending heart failure decompensation. The clinician must also keep in mind that small changes in natriuretic peptide levels (<50 % of baseline levels) could reflect biological variability in some patients and may not represent a forthcoming clinical event. Therefore, a detailed history, physical exam, and standard laboratory values are still very important in heart failure management.

With increasing data supporting the prognostic utility of natriuretic peptide, there have been several attempts to use natriuretic peptides to guide outpatient heart failure therapy with relative success. The first large-scale natriuretic peptide-guided therapy study was the STAR-BNP study by Jourdain et al. STAR-BNP was a multicenter study comparing the outcomes of BNP-guided therapy against standard clinical therapy. A total of 220 NYHA class II and III patients optimally managed with ACE inhibitors, beta-blockers, and diuretics were involved in the study. These patients were randomized to receive either BNP-guided therapy with a goal BNP of <100 pg/mL or standard clinical therapy according to guidelines at the time. The patients were followed for up to 15 months for a primary end point of heart failure-related death or admission. By the end of the study, the BNP-guided arm had significantly fewer patients reaching primary end point than the standard clinical therapy arm (24 % vs. 52 %, p < 0.001) [11]. The STAR-BNP study was followed by the BATTLESCARRED study, which was a large-scale study comparing NT-proBNP-guided therapy, intensive clinical management (treatment by a heart failure management team led by heart failure specialists), and usual care (treatment at the discretion of a primary care physician). A total of 366 patients were enrolled and followed for up to 3 years. The study found that 1-year mortality was significantly less in both the NT-proBNP-guided therapy arm (9.1 %) and the intensive clinical management arm (9.1 %) when compared to the usual care arm (18.9 %; p = 0.03). In addition, the study found that in patients less than 75 years of age, the 3-year mortality was significantly lower in the NT-proBNP-guided arm (15.5 %) when compared to both the intensive clinical management arm (30.9 %, p = 0.048) and the usual care arm (31.3 % and p = 0.021), highlighting the long-term benefit of natriuretic peptide-guided therapy [12]. The largest natriuretic peptide-guided heart failure therapy trial was the TIME-CHF trial, which was a prospective randomized study evaluating the effectiveness of NT-proBNP-guided therapy versus symptom-guided therapy with a total of 499 chronic heart failure patients followed for up to 18 months. This study found similar rates of survival free of all-cause hospitalizations between the NT-proBNP-guided therapy arm and symptom-guided therapy arm (41 % vs. 40 %, respectively; p = 0.39). Additionally, NT-proBNP-guided heart failure therapy led to higher rates of survival free of all-cause hospitalizations in patients aged 60–75 years (p < 0.02) [13]. A meta-analysis of natriuretic peptide-guided therapy confirmed that natriuretic peptide-guided therapy reduced all-cause mortality in patients <75 years old and reduced heart failure and cardiovascular hospitalization in all patients [14]. These studies have consistently shown the long-term effectiveness of natriuretic peptide-guided heart failure therapy, highlighting the potential benefit of adding natriuretic peptides to future heart failure treatment algorithms. This is reflected in the 2013 ACCF/AHA Guideline for the Management of Heart Failure, which gives a Class IIa level of evidence B recommendation to using natriuretic peptide-guided therapy [15].

Finally, using natriuretic peptides in screening for asymptomatic heart failure patients is also a possibility in the future, as many patients with left ventricular dysfunction would have elevations in natriuretic peptide levels prior to developing symptoms of heart failure. This would be a far more convenient and cost-effective method than the current gold standard for left ventricular dysfunction detection, the echocardiogram. There are many reasons why screening with natriuretic peptides would be beneficial. First of all, cardiac disorders are common and are a source of considerable morbidity and mortality. Additionally, natriuretic peptides are elevated early in the disease process, often before symptoms develop and thus can allow for early treatment. Finally, early treatment in heart failure is associated with better outcomes and is more cost-effective than delayed action. The future of natriuretic peptide use in the outpatient setting, whether it be managing chronic heart failure or screening for new cases, is bright, and the utility of natriuretic peptides is only going to increase with time.

In order to optimally use natriuretic peptides in clinical practice, the clinician must be aware of important caveats and limitations of their use:

BUN is a serum by-product of protein metabolism. It is probably one of the oldest prognostic biomarkers in heart failure. Urea is formed by the liver and carried by the blood to the kidneys for excretion. Diseased or damaged kidneys cause BUN to accumulate in the blood as the GFR goes down. Conditions such as hypovolemic shock, congestive heart failure, high-protein diet, and bleeding into the gastrointestinal tract will also cause BUN elevations. BUN plays a unique role as a short-term as well as long-term prognostic marker in patients with heart failure. In 2005, Fonarow et al. analyzed the ADHERE database for predictors of in-hospital mortality among 65,275 acute heart failure admissions. Of the 39 variables evaluated in this database, BUN ≥ 43 mg/dL was the single best predictor of mortality, followed by admission systolic blood pressure <115 mmHg and serum creatinine ≥2.75 mg/dL (243.1 μmol/L) [16]. Another study done by Aronson et al. in 2004, which involved 541 patients with acute heart failure, examined the prognostic utility of BUN, serum creatinine, BUN/creatinine ratio, and estimated creatinine clearance. There were 177 mortalities in this cohort and the mean follow-up period was 343 ± 185 days. The risk of all-cause mortality increased significantly with each quartile of BUN, with an adjusted relative risk of 2.3 in patients in the upper quartiles (p = 0.005). Creatinine and estimated creatinine clearance were not statistically significant predictors of mortality after adjustment for other covariates. BUN/creatinine ratio yielded similar prognostic information as BUN (adjusted relative risk = 2.3; p = 0.0007 for patients in the upper quartiles) [17]. As seen in these studies, elevated BUN levels are strongly associated with adverse outcomes in patients hospitalized for acute heart failure. Therefore, BUN levels should be considered in the routine prognostic evaluation of patients with acute heart failure.

Creatinine is a breakdown product of creatine phosphate in muscle tissue. It is usually produced at a fairly constant rate. Creatinine is cleared by the kidneys with little-to-no tubular reabsorption. Creatinine accumulates in the blood when GFR decreases in the setting of renal dysfunction. As a result, serum creatinine levels are commonly used to calculate the creatinine clearance, which is a surrogate for GFR and renal function. Since renal dysfunction is a negative prognostic factor in patients with heart failure, elevations of creatinine are associated with poor outcomes in heart failure patients. This was shown in a study by Vaz Perez et al. in 2009, involving 128 patients who were hospitalized for acute heart failure. In this study, elevated admission creatinine level was a strong predictor of both 1-year and 5-year mortality. For 1-year mortality, creatinine and ejection fracture were both independent predictors of mortality in multivariable analysis (p < 0.001), whereas body mass index and NYHA class did not reach statistical significance. In the multivariate analysis for 5-year mortality, creatinine and NYHA class were independent predictors of all-cause mortality (p < 0.001), whereas body mass index and age did not reach statistical significance [18]. In another study by Aronson et al. involving 467 patients with acute heart failure, persistent creatinine elevation above baseline was associated with significantly worse outcomes. Persistent creatinine elevation in this study was defined as ≥0.5 mg/dL increase in serum creatinine above baseline for more than 30 days. Transient creatinine elevation was defined as creatinine elevation ≥0.5 mg/dL above baseline that subsequently decreased to <0.5 mg/dL above baseline within 30 days. Persistent creatinine elevation was seen in 115 patients and transient creatinine elevation was seen in 39 patients. The 6-month mortality rates were 17.3 % in patients without creatinine elevation, 20.5 % in patients with transient creatinine elevation, and 46.1 % in patients with persistent creatinine elevation. Compared to patients’ stable creatinine (<0.5 mg/dL increase from baseline), the adjusted hazard ratio for mortality was 3.2 (p < 0.0001) in patients with persistent creatinine elevation [19]. These studies highlighted the fact that elevated creatinine level is a strong predictor of medium- and long-term mortality in patients with heart failure and can serve as a fast and inexpensive biomarker to help identify patients at high risk for mortality.