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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Clinical application of the natriuretic peptides in heart failure

Horng H. Chen* and John C. Burnett, Jr

Division of Cardiovascular Diseases, Department of Internal Medicine and Physiology, Mayo Clinic College of Medicine, Rochester, MN 55902, USA

* Corresponding author: Cardiorenal Research Laboratory, Guggenheim 915, Mayo Clinic and Foundation, 200 First St SW Rochester, MN 55905, USA. Tel: 1 507 284 4343; fax: 1 507 266 4710. E-mail address: chen.horng{at}mayo.edu


   Abstract
Top
 Abstract
Introduction
 Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
 Summary
 Acknowledgement
 References
 
The natriuretic peptides are a family of peptides each with a 17 amino acid disulphide ring structure, but are genetically distinct with diverse actions in cardiovascular, renal, and endocrine homeostasis. In humans, the family consists of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of myocardial cell origin, C-type natriuretic peptide (CNP) is of endothelial origin, and urodilatin (Uro) is thought to be derived from the kidney. Furthermore, natriuretic peptides have also been isolated from a range of other vertebrates. Notably, some were found in snake venoms: Dendroaspis angusticeps natriuretic peptide was detected in the venom of Dendroaspis angusticeps (the green mamba); CNP analogues were also cloned from the venom glands of snakes of the Crotalinae subfamily; Pseudocerastes persicus natriuretic peptide, isolated from the venom of the Iranian snake Pseudocerastes persicus and three natriuretic-like peptides (TNP-a, TNP-b, and TNP-c) isolated from the venom of Oxyuranus microlepidotus.

Human recombinant ANP (Carperitide) has been approved for the clinical management of acute decompensated CHF in Japan since 1995, human recombinant BNP (Nesiritide) has been approved for the same clinical indication in the USA since 2001, and human recombinant Uro (Ularitide) is currently undergoing phase III clinical trails in Europe.

As biomarkers, both BNP and NT-pro BNP are currently used clinically to aid the diagnosis of CHF, assessing the severity of CHF and risk stratification in patients with coronary artery diseases. In this review, we will attempt to provide an update on important issues regarding natriuretic peptides in CHF.

Key Words: Heart failure • Kidney • Biomarker • Natriuretic peptides


   Introduction
Top
 Abstract
 Introduction
Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
 Summary
 Acknowledgement
 References
 
The natriuretic peptides are a family of peptides each with a 17 amino acid disulphide ring structure, but are genetically distinct with diverse actions in cardiovascular, renal, and endocrine homeostasis.1 In humans, the family consists of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) of myocardial cell origin, C- type natriuretic peptide (CNP) is of endothelial origin, and urodilatin (Uro) is thought to be derived from the kidney2,3 (Figure 1). Furthermore, natriuretic peptides have also been isolated from a range of other vertebrates. Notably, some were found in snake venoms: Dendroaspis angusticeps natriuretic peptide was detected in the venom of Dendroaspis angusticeps (the green mamba);4 CNP analogues were also cloned from the venom glands of snakes of the Crotalinae subfamily;5 Pseudocerastes persicus natriuretic peptide isolated from the venom of the Iranian snake Pseudocerastes persicus,6 and three natriuretic-like peptides (TNP-a, TNP-b, and TNP-c) isolated from the venom of Oxyuranus microlepidotus.7


Figure 0261
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  		Figure 1 Amino acid sequences of the four human natriuretic peptides, h-ANP, h-BNP, h-CNP, and h-Urodilatin.

 
Human recombinant ANP (Carperitide) has been approved for the clinical management of acute decompensated congestive heart failure (CHF) in Japan since 1995, human recombinant BNP (Nesiritide) has been approved by the Federal Drug Administration (FDA) for the same clinical indication in the USA since 2001, and human recombinant Uro (Ularitide) is currently undergoing phase III clinical trails in Europe.

As biomarkers, both BNP and NT-pro BNP are currently used clinically to aid the diagnosis of CHF, assessing the severity of CHF and risk stratification in patients with coronary artery diseases. In this review, we will attempt to provide an update on important issues regarding natriuretic peptides in CHF.


   Physiological properties of the natriuretic peptides
Top
 Abstract
 Introduction
 Physiological properties of the...
Natriuretic peptides in the...
 Role of circulating natriuretic...
 Summary
 Acknowledgement
 References
 
ANP, BNP, and Uro bind to the natriuretic peptide-A receptor (NPR-A), which via 3',5'-cyclic guanosine monophosphate (cGMP) mediates natriuresis, vasodilatation, renin-inhibition, anti-mitogenesis, and positive lusitropism1 (Figure 2). CNP lacks natriuretic actions, but possesses vasodilating and growth-inhibiting actions via the guanylyl cyclase-linked natriuretic peptide-B receptor (NPR-B).8 All four peptides are cleared by the natriuretic peptide-C receptor (NPR-C) and degraded by the ectoenzyme neutral endopeptidase 24.11 (NEP), both of which are widely expressed in the kidney, lung, and vascular wall.9


Figure 0262
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  		Figure 2 Natriuretic peptide receptor organization and signal transduction mechanisms for ANP, BNP, and CNP with co-localization of NEP and angiotensin-converting enzyme at cell surface. RA, natriuretic peptide receptor A; RB, natriuretic peptide receptor B; RC, natriuretic peptide receptor C; GC, guanylyl cyclase; GTP, guanosine triphosphate; PDE, phosphodiesterase; PK, protein kinase; BK, bradykinin.

 
Functional role of the endogenous natriuretic peptides in cardiorenal homeostasis
Genetically altered knockout mice with either disruption of ANP production or deletion of the NPR-A receptor, which binds ANP and BNP, have elicited the role of endogenous natriuretic peptides in cardiorenal homeostasis. These studies have been complemented by pharmacological studies antagonizing the NPR-A/B receptor. In these key investigations, a unifying understanding of the importance of the natriuretic peptides system in cardiovascular and renal homeostasis has been established. Specifically, genetic modification of the natriuretic peptide system resulted in either salt-sensitive10 or salt-insensitive11 hypertension, an impaired renal response to acute volume expansion, ventricular hypertrophy, and sudden death.12 The important relationship between the natriuretic peptide system and human hypertension is further supported by studies which showed that restriction fragment length polymorphism exists in the second intron of the human ANP gene, a candidate gene for familial susceptibility to hypertension and also that there are restriction fragment length polymorphisms at the ANP gene locus in hypertension associated with primary aldosteronism.13 Tamura et al.14 also demonstrated in a BNP gene knockout model that these mice have significant ventricular fibrosis, despite normal haemodynamics. Furthermore, experimental pharmacological studies antagonizing the NPR-A/B receptor have demonstrated that the endogenous natriuretic peptides have vasodilating, natriuretic, diuretic, lusitropic, and renin-inhibiting properties that are essential in maintaining cardiorenal homeostasis in CHF. Specifically, Stevens et al.15 established that the transition from experimental mild CHF to severe CHF could be accelerated utilizing a natriuretic peptide receptor antagonist which resulted in premature sodium retention, impaired renal natriuretic response to volume expansion, activation of the renin–angiotensin–aldosterone system (RAAS), and further increases in cardiac filling pressures.

Physiological properties of exogenously administered natriuretic peptides
Since the landmark study by de Bold et al.16 in 1981 in which they injected partially purified extract of rat atria into rats, there has been numerous studies defining the physiological properties of exogenously administered natriuretic peptides. Initial studies with synthetic ANP, concurred with the findings of de Bold et al., demonstrating that the administration of ANP resulted in vasodilatation, reduction in cardiac filling pressure, natriuresis, diuresis associated with increased renal blood flow, increased glomerular filtration rate, and suppression of renin.17 Subsequent studies with BNP and Uro showed that they had similar properties with ANP.18 Other less well known but important physiological effects of the natriuretic peptides including pro-lusitorpic,19 sympatho-inhibitory,20 anti-proliferative,21,22 anti-ischaemic,22 and anti-inflammatory23 have all been well established in experimental and human studies.


   Natriuretic peptides in the therapeutics of CHF
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 Abstract
 Introduction
 Physiological properties of the...
 Natriuretic peptides in the...
Role of circulating natriuretic...
 Summary
 Acknowledgement
 References
 
With the known favourable cardiorenal and humoral physiological effects, strategies have emerged to utilize the natriuretic peptide system in the treatment of disorders of cardiorenal function such as CHF.

Bolus injection and continuous infusion of ANP, BNP, and Uro in humans with CHF have been pursued as therapeutic approaches to CHF over the past decade. These investigations have demonstrated that the natriuretic peptides decreases pulmonary artery pressure, pulmonary capillary wedge pressure (PCWP), right atrial pressure, mean arterial pressure (MAP), and increases cardiac index, urine volume, and urine sodium excretion (UNaV) without associated adverse neurohumoral activation.18,24–26 As a result of these studies, human recombinant ANP (Carperitide) has been approved for the clinical management of acute decompensated CHF in Japan since 1995, human recombinant BNP (Nesiritide) has been approved for the same clinical indication in the USA since 2001, and human recombinant Uro (Ularitide) is currently undergoing phase III clinical trails in Europe.

The clinical trails that led to the approval of human recombinant BNP (Nesiritide) by the FDA in 2001 for the management of acute decompensated CHF included the Efficacy and Comparative trials published by Colucci et al.25 and subsequently the multicenter Vasodilation in the Management of Acute Congestive Heart Failure (VMAC) trial published by Young et al.26 In both the Efficacy and Comparative trials, patients who required hospitalization and intravenous (IV) therapy for decompensated CHF were enrolled. The patients were randomized to placebo or Nesiritide 0.3 µg/kg IV bolus followed by an infusion of 0.015 µg/kg/min, or Nesiritide given as a 0.6 µg/kg bolus followed by an infusion of 0.03 µg/kg/min, for 6 h. Nesiritide caused a dose-dependent decrease in PCWP, systemic vascular resistance and systolic blood pressure, and a dose-dependent increase in cardiac index. No change in heart rate was noted. Mean urine output was higher in the Nesiritide groups compared with placebo. Global status improved in patients receiving both Nesiritide doses according to the judgement of the treating physician and the patient. Similarly, dyspnoea and fatigue were rated as improved in more patients receiving Nesiritide at both dosages than those receiving placebo. However, both symptomatic and asymptomatic hypotension were reported more frequently in the Nesiritide group than in the standard therapy group. As a result of the increased incidence of hypotension, in the subsequent VMAC trial, a lower dose of Nesiritide was used (a bolus of 2 µg/kg followed by an infusion of 0.01 µg/kg/min). The primary endpoints were change in the patient's self-evaluation of dyspnoea in the entire population and absolute change in PCWP in the catheterized patients after 3 h of therapy. Patient's self-assessment of dyspnoea at 3 h had improved in patients treated with Nesiritide compared with patients receiving placebo. Furthermore, PCWP was lower in the Nesiritide group at 3 h compared with placebo. Importantly, the incidence of both symptomatic and asymptomatic hypotension was similar between the two groups.

Controversies in the clinical use of Nesiritide for the management of CHF
Although pre-clinical and early clinical studies have demonstrated the renal-enhancing effects of systemic IV administration of BNP, the clinical trials which led to the FDA approval of Nesiritide for the management of acute CHF have been conflicting with regard to the renal-enhancing properties of Nesiritide. Specifically, a recently study reported that IV Nesiritide did not improve renal function in 15 patients with worsening renal function in response to furosemide.27 Furthermore, a meta-analysis of the clinical trials even suggested that Nesiritide might even be detrimental to renal function in patients with acute decompensated CHF.28

The discrepancy in the renal actions of Nesiritide reported is most likely multifactorial; however, two potential explanations are as follows.

First, critical review of the pre-clinical,18 early clinical,24,29,30 and clinical studies suggests that the lack of renal effects of Nesiritide in some of the clinical studies may be in part due to the fact that the doses used in the clinical studies resulted in significant decrease in blood pressure and hence renal perfusion pressure. Supporting this hypothesis is a study by Chen et al. in experimental CHF, which demonstrated that a low dose of subcutaneously administered BNP, which did not lower blood pressure, had more beneficial renal haemodynamic profile than a higher dose that lowered blood pressure.31 Furthermore, Chen et al. have recently completed a retrospective study suggesting that the use of non-hypotensive low-dose Nesiritide with low-dose furosemide therapy in acute decompensated CHF patients with renal dysfunction improved renal function when compared with the standard dose Nesiritide which resulted in the decrease in blood32 pressure.

Secondly, another possible explanation for the lack of renal-enhancing effects of Nesiritide in some patients with acute decompensated CHF may be related to the severity of the CHF. Both humans and animal models with severe overt CHF are characterized by an attenuated natriuretic response to endogenous and exogenous natriuretic peptides9,33 when compared with mild CHF. Indeed, it has been suggested that the diminished renal response to the cardiac natriuretic peptides play an important role in the pathophysiology of sodium retention and systemic and renal vasoconstriction observed in severe heart failure, thus contributing to disease progression.15 The mechanisms responsible for the renal hyporesponsiveness to cardiac natriuretic peptides in severe CHF are most likely multifactorial and include decreased renal perfusion pressure,34 increased renal sympathetic nerve activity, receptor down-regulation, post-receptor events leading to reduced production of cGMP or increased cGMP degradation, enhanced enzymatic degradation of the natriuretic peptides by NEP,35 and increased activity of functional antagonists to the natriuretic peptides such as the RAAS.36 NEP is a membrane-bound metalloprotease whose main substrate is the natriuretic peptides. NEP has a wide tissue distribution, including the kidney, lung, endothelial cells, and brain. Indeed, the highest concentrations of NEP have been localized to the brush border vesicles of the renal proximal tubules.37 NEP and vasopeptidase inhibitors have been developed for the management of CHF, although pre-clinical and early clinical studies have been encouraging, late clinical studies have been disappointing. Unfortunately, like exogenous natriuretic peptides, the renal actions of NEP inhibition are also attenuated in experimental overt CHF when compared with the mild CHF.9 A strategy to maximize the natriuretic peptide system is to combine the administration of exogenous natriuretic peptide with vasopeptidase inhibitor or NEP inhibitor. Indeed, such a strategy was tested in a study by Chen et al.38 in experimental CHF which demonstrated that the combination of BNP and a vasopeptidase inhibitor resulted in a synergistic improvement in renal function. Type V phosphodiesterase metabolizes cGMP, the second messenger of the natriuretic peptides, and has been reported to increase in severe experimental CHF which therefore could mediate the decrease in cGMP generation to the natriuretic peptides in severe CHF. Studies by Supaporn et al.39 in isolated glomeruli from kidneys of dogs with severe CHF demonstrated that ANP-induced cGMP generation was attenuated when compared with control. Thus, these studies support an important role for renal cGMP phosphodiesterase modulation of the renal response to endogenous and exogenous natriuretic peptides. Therefore, another strategy to overcome the renal resistance to the natriuretic peptides is the combination of exogenous natriuretic peptide with cGMP phosphodiesterase inhibition. A preliminary report by Chen et al. suggested that such a strategy indeed has favourable renal actions in experimental severe CHF.40

Although the haemodynamic actions of exogenous natriuretic peptides in CHF have been well defined, further prospective randomized controlled studies are warranted to further define their renal actions. Specifically, non-hypotensive lower doses of the natriuretic peptides should be tested. Furthermore, strategies to maximize the natriuretic peptide system such as the combination of natriuretic peptides with vasopeptidase or NEP or cGMP phosphodiesterase inhibitor to enhance renal function in patients with CHF need to be explored.

Future directions: use of chronic BNP therapy in cardiovascular diseases
As discussed earlier, mouse models of altered production of BNP or disruption of its receptor together with laboratory-based and clinical research with infusions of BNP have supported its cardiorenal protective properties under certain experimental and clinical conditions related to heart failure. Although the IV administration of BNP as well as ANP is an accepted clinical practice for acute decompensated heart failure, the concept of chronic administration of BNP particularly in delaying the progression of heart failure in which early ventricular dysfunction targeted when renal responsiveness to BNP is well intact is beginning to emerge. This is also a result of the view that inadequate production of BNP may occur in heart failure as well as recent evidence that there may be altered molecular forms of BNP with reduced biological activity of BNP in advanced heart failure with an actual absence of the biologically active BNP 32.41 The paradigm of chronic peptide administration in human disease is not a new one. Diabetes is such a paradigm where inadequate production of the protein insulin requires chronic administration of synthetic insulin to maintain optimal metabolic balance.

We have recently addressed the concept of defining the cardiorenal and humoral actions of repeated short-term administration of subcutaneous (SQ) BNP administration during the evolution of experimental heart failure.31 We utilized a unique large animal model of heart failure that mimics human asymptomatic left ventricular dysfunction (ALVD). Our rational was based on BNP as a vasodilating, natriuretic, renin-inhibiting and lusitropic peptide of cardiac origin. We found that plasma BNP and cGMP rapidly increased after acute SQ BNP administration with increases in urinary sodium excretion, urine flow, and renal blood flow in association with reductions in cardiac filling pressures. After 10 days of repeated short-term administration of SQ BNP, cardiac output was increased and systemic vascular resistance and PCWP were decreased when compared with untreated dogs with heart failure. Thus, this study demonstrated for the first time that repeated short-term administration of SQ BNP administration during the evolution of experimental ALVD resulted in an improvement of cardiovascular haemodynamics supporting the concept of novel chronic administration of BNP in the therapeutics of heart failure.

This experimental study in an animal model of evolving heart failure was followed by a study to asses the safety and efficacy of repeated doses of SQ BNP in human NYHA class II–III CHF. This short-term 3-day study defined the cardiorenal and humoral responses to SQ BNP administered every 12 h with a total of five doses over 72 h in a single blind placebo control design.42 The initial saline placebo resulted in no change in measured parameters. The first dose of BNP increased cardiac output and reduced systolic blood pressure without a change in heart rate. Plasma BNP and urinary cGMP excretion increased with natriuresis and diuresis. Both plasma renin activity and aldosterone decreased. These favourable biological responses were observed with the fifth dose 3 days after the initial dose. Thus, we concluded that SQ administration of BNP in human CHF has efficacy and safety warranting further investigations with a goal of attempting to delay the progression of heart failure focusing on earlier stages of heart failure with a kidney which is highly responsive to the cardiac peptide BNP.

Most recently, we have advanced an exciting concept of the development and use of an orally available human BNP. Here, we address the feasibility and the biological activity of oral BNP utilizing proprietary technology using short amphiphilic oligomers covalently attached to BNP.43 Oral BNP increased plasma BNP, activated plasma cGMP, and reduced MAP in conscious normal dogs. Thus, although BNP is an important IV drug in treating hospitalized patients with acute decomposition, an oral dosage form may broaden the application of this therapy to patients with various stages in the progression of heart failure and be an important preventive strategy in evolving heart failure. More over, recognizing its anti-fibrotic actions as well as its blood pressure lowering properties, the use of oral BNP as a therapeutic for human heart hypertension as well as heart failure warrants further research.


   Role of circulating natriuretic peptides as biomarkers in CHF
Top
 Abstract
 Introduction
 Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
Summary
 Acknowledgement
 References
 
On the basis of its elevation in chronic CHF, circulating ANP and BNP have emerged as an important diagnostic and prognostic serum markers in CHF. Initial studies have demonstrated that elevated plasma ANP correlates with the functional class of symptomatic CHF. Subsequently, studies focused upon the N-terminus of pro-ANP (N-ANP) which is the non-biologically active fragment of the pro-hormone and co-released with the biologically active 28 amino acid C-terminal ANP (C-ANP). N-ANP is cleared more slowly and thus circulates at higher concentrations than the biologically active C-ANP. Moreover, it is more stable in vitro than C-ANP. Lerman et al.44 examined its specificity and sensitivity as a diagnostic test in identifying subjects with ALVD as documented prospectively with radionuclide angiography and clinical characterization. These studies demonstrated that N-ANP was elevated consistently in NYHA class I patients with ALVD and was more sensitive and specific than C-terminal ANP, thus emerging as an important non-invasive serum marker in the identification of patients with ALVD. With the known elevation of plasma BNP in CHF, studies then focused upon its diagnostic utility in CHF. Davis et al.45 reported that elevated BNP was an excellent discriminator of cardiac and non-cardiac dyspnoea. In studies by Yamamoto et al.,46 BNP emerged as superior to either N-terminal or C-terminal ANP as a marker for ventricular systolic or diastolic dysfunction and ventricular hypertrophy in patients with, or at risk for, cardiac disease. Specifically, BNP demonstrated greater sensitivity and specificity than N-terminal or C-terminal ANP for reductions in ejection fraction or increases in left ventricular (LV) mass. Following a similar rationale as with N-ANP, Richards et al.47 reported that NT-Pro-BNP measured 2–4 days after myocardial infarction independently predicted LV function and 2-year survival. Currently, there are three different diagnostic tests for the measurement of BNP approved by the FDA for aiding in the diagnosis of CHF. A rapid point-of-care test for determination of BNP concentrations in human plasma was introduced in 2000 (Triage BNP; Biosite Diagnostics, San Diego, CA, USA). The Shionogi BNP test is an one-step immunoradiometric assay that uses two different monoclonal antibodies that recognize the C-terminal structure and the disulphide bond mediated ring structure. The test requires ~20 h. The FDA has also approved a fully automated blood test for quantification of N-terminal pro-BNP (NT-Pro-BNP) in 2002 (Roche Diagnostics). Since 2000, there have been an explosion of studies and papers published measuring BNP or NT-pro-BNP in almost every disease category in cardiology. A detail review of all the literature is beyond the scope of this review, therefore we will only focus on key studies supporting its approved role and studies evaluating future potential use in CHF.

Aid in diagnosis of CHF
Although the diagnosis of CHF is based on clinical signs and symptoms, it is often difficult both in the emergency room and outpatient setting to definitively diagnosed CHF in patients presenting with dyspnoea. The value of plasma BNP for distinguishing between CHF and a pulmonary cause of dyspnoea was best evaluated in the Breathing Not Properly (BNP) study.48 In the 1586 patients who presented to the emergency department or urgent care setting with a major complaint of acute dyspnoea, plasma BNP was markedly higher in patients with clinically diagnosed CHF compared with those without CHF (mean 675 vs. 110 pg/mL). A plasma BNP >100 pg/mL diagnosed HF with a sensitivity, specificity, and predictive accuracy of 90, 76, and 83 percent, respectively. The predictive accuracy of plasma BNP for CHF was equivalent to or better than other parameters such as cardiomegaly on chest X-ray, a history of CHF, or rales on physical examination and was better than the widely used NHANES and Framingham criteria for the diagnosis of HF (83 vs. 67 and 73%, respectively). The cost-effectiveness of the use of BNP assay in the aid of diagnosis of CHF was reported in the BASEL study from Sweden.49 Patients presenting with acute dyspnoea (n=452) were randomized to a diagnostic strategy including plasma BNP measurement (Biosite Triage BNP test) or standard practice without BNP. The final discharge diagnosis was CHF in 48%. Significantly fewer patients in the BNP group than the control group were hospitalized (75 vs. 85%) or admitted to the intensive care unit (15 vs. 24%). The median length of stay was significantly shorter in the BNP group (8 vs. 11 days) and the cost of treatment was significantly less ($5410 vs. $7264). The value of natriuretic peptides in assessment of patients with possible new CHF was evaluated by Cowie et al.50 in the primary care outpatient setting. One hundred and twenty-two patients with suspected CHF underwent an extensive evaluation by an independent panel of cardiologists blinded to the BNP data. BNP, ANP, and N-ANP were evaluated. Although all peptides correlated with the diagnosis, BNP had the highest sensitivity (97%) and specificity (84%) for the diagnosis of CHF. Lainchbury et al.51 compared the utility of a number of different BNP and NT-Pro-BNP assays for the diagnosis of CHF in 205 patients (mean age 70±14 years) presenting to the emergency department with acute dyspnoea. Although the scale of values for BNP measured by the Biosite Triage BNP test and the Roche assay for NT-Pro-BNP were different, they were highly correlated (r=0.902, P<0.0001. Further, in the Lainchbury study, the predictive characteristics were very similar with the area under the receiver operating characteristic curve being identical for each assay.

The following variables need to be considered when using BNP or NT-Pro-BNP to aid in the diagnosis of CHF. Multiple studies have identified various factors that may affect the levels; these include age,52 gender,52 obesity,53 concurrent medications, and renal function. Furthermore, there are subtle differences between the assays system. Both BNP and NT-Pro BNP are much better as a ‘rule out’ test than as a ‘rule in’ test for CHF. Lastly, like any other blood test, it should not be used as a stand alone test but rather in combination with clinical signs and symptoms and other investigations.

Prognostic marker in CHF
In all the four stages of CHF, from Stage A to D, plasma BNP or NT-Pro-BNP provides prognostic information. In a substudy of the Val-HeFT trial, those with a plasma BNP concentration in the highest quartile (≥238 pg/mL) at baseline had a significantly greater mortality at 2 years than those with a plasma BNP in the lowest quartile (<41 pg/mL) (32.4 vs. 9.7%).54 In patients hospitalized for CHF, pre-discharge plasma BNP level is predictive of death or re-admission. A meta-analysis of 19 studies in which plasma BNP was used to estimate the relative risk of death or cardiovascular events in patients with CHF reported that for every 100 pg/mL increase in plasma BNP there was an associated 35% increase in the relative risk of death.55 Furthermore, in multivariable models, plasma BNP was a better predictor of survival than traditional risk factors such as NYHA class and LV ejection fraction.

Monitoring of therapy for CHF
On the basis of the fact that BNP is an important prognostic indicator in CHF, the utility of serial BNP measurements to monitor the response therapies is currently being investigated. A substudy of the Val-HeFT trial suggested that patients with a reduction in plasma BNP at 24 months when compared with baseline had the best prognosis.54 In a study by Troughton et al.,56 69 patients with class II–IV symptoms were randomized to treatment guided by either plasma N-BNP concentration or standardized clinical assessment. Patients were followed for a minimum of 6 months (median 9.5 months). The BNP group had fewer cardiovascular events (death, hospital admission, or acute decompensation) compared with clinical assessment only group (19 vs. 54, P= 0.02). BNP-guided treatment also delayed time to first event compared with the conventional therapy group. Although it is tempting to use serial measurements of BNP or NT-Pro BNP to monitor therapy, we should await the results of the ongoing clinical trial both in the US and New Zealand.

Screening for Stage B CHF
At least three large population-based study have been completed to determine the role of using BNP or NT-Pro-BNP as a screening tool for Stages A and B CHF; these include the MONICA study,57 Framingham Heart Study,58 and the Olmsted County study.59 The investigators of the Framingham Heart Study and the Olmsted County study concluded that BNP did not appear promising as a screening tool for systolic dysfunction or elevated LV mass in the general population or in higher risk subsets of the general population. Although these studies do not indicate robust predictive characteristics of BNP for population screening, Heidenreich et al.60 reported that, at least in men, checking a single screening BNP may be ‘cost-effective’ but only in elderly men. This analysis estimated not only the cost of the BNP test, confirmatory echo, and subsequent diagnostic tests and therapy but also estimated the benefit in terms of quality-adjusted years of life saved.


   Summary
Top
 Abstract
 Introduction
 Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
 Summary
Acknowledgement
 References
 
The natriuretic peptides are family of peptides with great potential both as therapeutic agents and as biomarkers. Despite the impressive progress over the past decade, more studies are needed to define fully the true therapeutic and diagnostic potential of this unique family of endogenous peptides.


   Acknowledgement
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 Abstract
 Introduction
 Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
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 Acknowledgement
References
 
This research was supported by grants HL 36634 from the National Institutes of Health, Miami Heart Research Institute, Mayo Foundation, and the American Heart Association Scientist Development Grant awarded to H.H.C.

Conflict of interest: H.H.C. has received research grants from Scios Incorporated and Cardiopep. J.C.B. has received research grants from Scios Incorporated, Unipath and Cardiopep, and is a consultant for Abott Laboratory.


   References
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 Physiological properties of the...
 Natriuretic peptides in the...
 Role of circulating natriuretic...
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 Acknowledgement
 References
 

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