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(Circulation. 2007;116:e99-e109.)
© 2007 American Heart Association, Inc.

Special Report

National Academy of Clinical Biochemistry Laboratory Medicine Practice Guidelines: Clinical Utilization of Cardiac Biomarker Testing in Heart Failure

WRITING GROUP: W.H. Wilson Tang, MD; Gary S. Francis, MD; David A. Morrow, MD, MPH; L. Kristin Newby, MD, MHS; Christopher P. Cannon, MD; Robert L. Jesse, MD, PhD; Alan B. Storrow, MD; Robert H. Christenson, PhD; COMMITTEE MEMBERS; Robert H. Christenson, PhD, Chair; Fred S. Apple, PhD; Christopher P. Cannon, MD; Gary S. Francis, MD; Robert L. Jesse, MD, PhD; David A. Morrow, MD, MPH; L. Kristin Newby, MD, MHS; Jan Ravkilde, MD, PhD; Alan B. Storrow, MD; W.H. Wilson Tang, MD; Alan H.B. Wu, PhD

	Introduction

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 

I. Overview of Heart Failure...e99

   A. Context of Biochemical Marker Testing in Heart Failure...e99

   B. Background and Definition of Terms...e100

   C. B-type Natriuretic Peptide (BNP) and Amino- Terminal proB-Type Natriuretic Peptide (NT-proBNP) Metabolism and Measurement...e100

II. Use of Biochemical Markers in the Initial Evaluation of Heart Failure...e101

   A. Diagnosis of Heart Failure...e101

1.       BNP and NT-proBNP for Diagnosis of Acute Decompensated Heart Failure...e102
   
2.       BNP or NT-proBNP for Confirmation of the Heart Failure Diagnosis...e103
   

   B. Risk Stratification of Heart Failure...e103

1.       Risk stratification of Patients With and Without Heart Failure Using BNP or NT-proBNP...e103
   
2.       Risk Stratification of Patients With Heart Failure Using Cardiac Troponin...e104
   

III. Use of Biochemical Markers in Screening for Cardiac Dysfunction...e104

   A. BNP or NT-proBNP for Screening Heart Failure and Dysfunction...e104

   B. Approaches for Screening for Cardiac Dysfunction...e104

IV. Use of Biochemical Markers in Guiding Management of Heart Failure...e105

   A. Monitoring Therapy Using BNP or NT-proBNP Guidance...e105

V. References...e105

	I. Overview of Heart Failure

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 
A. Context of Biochemical Marker Testing in Heart Failure
Biochemical marker testing has revolutionized the approach to diagnosis and management of heart failure over the past decade. There is an unsurpassed excitement in the heart failure community that significant advances in our understanding of currently available and future cardiac biomarkers will facilitate improved characterization of heart failure disease states and promote individualized therapy in heart failure and beyond. However, like most novel diagnostic tests, the promising findings from pivotal trials have met with ongoing challenges when applied in the clinical setting.

The material discussed in this guidelines document addresses clinical use of BNP/NT-proBNP and cardiac troponin testing in the context of heart failure diagnosis, risk stratification and management, including therapeutic guidance in adult (>18 year-old) patients. Together with the associated document titled "National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure", these recommendations are aimed at appropriate utilization of this testing by both practicing clinicians and laboratorians. The committee feels that dissemination of this guidance to the clinical and laboratory communities will improve communication and ultimately care and outcomes of patients with heart failure. Although providing specific tools for implementation is complicated, the guidelines are designed to be direct and succinct to facilitate implementation. The committee feels that education and dissemination are the major barriers to over- or under-use of natriuretic peptide testing. For this reason, there are plans for wide dissemination of the recommendations contained herein; the committee believes such dissemination will assist in educating users on the advantages and caveats of BNP and NT-proBNP measurement. Regarding costs as an example, the direct per-test cost for BNP or NT-proBNP measurement is approximately $50 (2007 United States [US] currency). Although somewhat controversial, there is evidence that use of natriuretic peptide testing in the context of heart failure decreases cost without increasing patient risk.^1,2 Costs were considered by the committee in formulating recommendations; however, the costs were considered modest compared with the total care of heart failure patients, and this view is supported by evidence.^1,2

It is most important to emphasize that validity of test results must complement clinical findings to define a disease process. Thus, biochemical marker testing (such as BNP and NT-proBNP measurement) is not a stand-alone test, and must be used and interpreted in a larger clinical context, with confounding factors taken into account. Used appropriately in this context, the health benefits of testing far outweigh the side effects and risks of having knowledge of BNP and NT-proBNP levels. Use of cardiac troponin testing as it pertains to the heart failure population will also discussed primarily in its role for risk stratification.

B. Background and Definition of Terms
Heart failure is a complex clinical syndrome that can result from any structural or functional cardiac disorder that impairs the ability of the ventricles to fill with or eject blood.³ It is a growing and costly problem, affecting 2% to 3% of the total US population. Moreover, it is estimated that only 50% of all patients survive up to 4 years.⁴ The increasing prevalence of heart failure is due to the aging population as well as the marked increase in survival of patients who suffered from myocardial infarction. Conservative estimates suggest that over 50% of cases have an ischemic origin, while up to 75% of cases have hypertension as a major contributing factor. The cost of heart failure is estimated to be $100 billion a year in Europe and the US, 70% of which is due to hospitalization.^3–5

The diagnosis of heart failure is a bedside diagnosis based on clinical signs and symptoms rather than any stand-alone test results. However, a substantial proportion of the patients referred to cardiologists from primary care physicians have been originally misdiagnosed with conditions other than heart failure. Therefore, clinical biomarker testing in the setting of heart failure has three important goals: 1) to identify possible underlying (and potentially reversible) causes of heart failure; 2) to confirm the presence or absence of the heart failure syndrome; and 3) to estimate the severity of heart failure and risk of disease progression.

Over the last decade, natriuretic peptides, particularly BNP and its amino-terminal co-metabolite, NT-proBNP, have been shown to be particularly useful in confirming or refuting the diagnosis of heart failure as well as stratifying long-term risk profiles. Several novel cardiac, metabolic and inflammatory biomarkers have emerged in the heart failure literature, such as C-type natriuretic peptide,⁶ endothelin-1,⁷ cardiac troponin,⁸ high-sensitivity C-reactive protein (hsCRP),^9,10 apelin,^11,12 myotrophin,¹³ urotensin-II,^14–16 adrenomedullin^17,18 and mid-regional pro-adrenomedullin,¹⁹ cardiotrophin-1,^20,21 urocortin,²² soluble ST2 receptor,²³ myeloperoxidase (MPO),²⁴ copeptin,^19,25 growth differentiation factor-15 (GDF-15),²⁶ lymphocyte G-protein coupled receptor kinases (GRK-2),²⁷ galectin-3,²⁸ mid-regional pro-A-type natriuretic peptide and other circulating forms,^19,29 and many others. However, their clinical role remains to be determined and validated (Table). Therefore, we will focus our discussion on the utility of testing BNP and its associated metabolite NT-proBNP in heart failure, with some mentioning of other cardiac biomarkers in specific contexts.

View this table: [in this window] [in a new window]   Selected Biochemical Markers Currently Available or Under Study for Clinical Diagnosis, Management, and Risk Stratification of Heart Failure

C. BNP and NT-proBNP Metabolism and Measurement
Since a large body of knowledge in biochemical marker testing specific to patients with heart failure will involve BNP and NT-proBNP, we will specifically discuss the metabolism and measurement of these markers. BNP and NT-proBNP belong to a family of naturally occurring hormones known as natriuretic peptides. Although BNP is co-expressed in secretory vesicles with A-type natriuretic peptide and the stimuli for expression is complex, BNP expression is augmented primarily by increase in wall tension in response to pressure (and volume) overload in both the atria and the ventricles. Therefore, elevated blood BNP and NT-proBNP levels occur in the setting of elevated filling pressures in patients with cardiac dysfunction, and can provide relatively reliable diagnostic and prognostic information.³⁰

It is clear from the existing literature that blood natriuretic peptide levels are reduced following long-term treatment with angiotensin converting enzyme (ACE) inhibitors,^31,32 angiotensin-II receptor blockers³³ and spironolactone.^34,35 This finding is most likely due to reduction in filling pressures and/or reversal of the pathological remodeling process that occurs following neurohormonal blockade. However, responses in natriuretic peptide levels to beta-adrenergic blockers have been mixed – while the majority of the literature points to reduction of blood natriuretic peptide levels with long-term treatment with beta-adrenergic blockers, transient elevation of blood natriuretic peptide levels have been observed with their initiation.³⁶

Several commercial laboratory platform-based and point-of-care assays have become available for BNP testing in the clinical setting as an aid to the diagnosis of heart failure and for providing prognostic information (Table). For example, blood BNP of <100 pg/mL or a blood NT-proBNP of <300 pg/mL have high negative predictive values in ruling out the diagnosis of heart failure among patients presenting with dyspnea.^37,38 As stated earlier, in this document, the term "natriuretic peptide" in subsequent discussions will refer to both BNP and NT-proBNP unless otherwise specified.

There are several practical considerations in the use of blood natriuretic peptide testing in the clinical settings. First, the reference ranges for natriuretic peptides assays vary depending on the assay method employed and the nature of the control population. The units expressed in the natriuretic peptide literature including mol/L and pg/mL, and the commonly used research assay (Shionogi) often reports values that are 15% to 20% below that of the commercial assays (Biosite and Abbott).³⁹ Differences in results between these assays have been attributed to the different epitopes identified by antibodies used in different immunoassays.⁴⁰ These variations have made direct comparison among study results difficult, and careful consideration of the type(s) of assay used when interpreting values reported in the literature is warranted (see National Academy of Clinical Biochemistry and IFCC Committee for Standardization of Markers of Cardiac Damage Laboratory Medicine Practice Guidelines: Analytical Issues for Biomarkers of Heart Failure).

Second, a wide variety of clinical factors have been shown to influence blood natriuretic peptide levels, including age and sex,^39,41–43 renal function,^43–48 body habitus,^49–51 thyroid function,^52,53 and anemia.⁵⁴ Obesity, in particular, has been associated with lower blood BNP and NT-proBNP levels across the spectrum of heart failure, and should be interpreted with caution, especially in ruling out cardiac causes of dyspnea. Preexisting cardiac conditions such as prior history of heart failure,⁵⁵ rhythm abnormalities,^42,56–58 and underlying etiology of heart failure⁵⁹ may also influence the diagnostic accuracies. The relative influence of these factors in relation to the degree of cardiac dysfunction remains highly debated, and can be different in various clinical settings (overall, confounding effects are less apparent in the setting of acute exacerbation of heart failure). Furthermore, diastolic dysfunction, mitral regurgitation, right ventricular dysfunction, recent heart surgery, and other cardiac structural or functional abnormalities can significantly influence blood natriuretic peptide levels.^60–63

Third, although several studies have demonstrated excellent statistical correlations between the BNP and NT-proBNP assays,^64,65 there were noticeable differences. particularly with regard to their half-lives, intra- and inter-individual variability,^66,67 and differences in their production and renal clearance. However their overall diagnostic and prognostic abilities appeared to be comparable in the clinical setting. There are also differences in peptide stability. Currently, there is no direct "conversion" between the two assay types, let alone between different assays within the same peptide.

When applied in conjunction with the clinical history, physical examination and other tools available to physicians, cardiac biomarkers are valuable in achieving clinical objectives as outlined below.

	II. Use of Biochemical Markers in the Initial Evaluation of Heart Failure

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 
A. Diagnosis of Heart Failure
Recommendations for Use of Biochemical Markers for Diagnosis of Heart Failure

Class I

1. BNP or NT-proBNP testing can be used in the acute setting to rule out or to confirm the diagnosis of heart failure among patients presenting with ambiguous signs and symptoms. (Level of Evidence: A)
   

Class IIa

1. BNP and NT-proBNP testing can be helpful to exclude the diagnosis of heart failure among patients with signs and symptoms suspicious of heart failure in the non-acute setting. (Level of Evidence: C)
   

Class III

1. In diagnosing patients with heart failure, routine blood BNP or NT-proBNP testing for patients with an obvious clinical diagnosis of heart failure is not recommended. (Level of Evidence: C)
   
2. In diagnosing patients with heart failure, blood BNP or NT-proBNP testing should not be used to replace conventional clinical evaluation or assessment of the degree of left ventricular structural or functional abnormalities (eg, echocardiography, invasive hemodynamic assessment). (Level of Evidence: C)
   

1. BNP and NT-proBNP for Diagnosis of Acute Decompensated Heart Failure
Most of the early studies of natriuretic peptides have focused on the diagnostic role of BNP or NT-proBNP testing among patients presenting with signs and symptoms of heart failure. The utility of blood BNP or NT-proBNP testing in the initial evaluation of patients with heart failure in the acute setting has been well established by several prospective multi-center clinical studies. In the multicenter Breathing-Not-Properly Study, using a BNP level of 100 pg/mL as a diagnostic "cut-off" gave a sensitivity of 90%, specificity of 76% and a diagnostic accuracy of 81% in determining a heart failure etiology of acute dyspnea, which was superior to clinical assessment alone in a series of 1,586 patients presenting to the emergency department with acute dyspnea⁶⁸ (Figure, A). In a recent randomized controlled trial comparing a diagnostic strategy involving blood BNP testing versus clinical assessment alone, blood BNP testing in the emergency department improved the evaluation and treatment of patients with acute dyspnea, reducing the time to discharge and the total cost of treatment.¹ Similar findings were reported in the primary care setting in which blood NT-proBNP testing improved the diagnostic accuracy of acute heart failure by general practitioners.⁶⁹ The equivalent role of NT-proBNP testing was confirmed in the PRIDE (ProBNP Investigation of Dyspnea in the Emergency Department) study, in which blood NT-proBNP testing was performed in 600 patients presenting to the Emergency Department with acute dyspnea. NT-proBNP at cut-points of >450 pg/mL (ages <50 years) and >900 pg/mL (ages 50 years) were highly sensitive and specific for the diagnosis of acute heart failure, while <300 pg/mL was optimal for ruling out acute heart failure (negative predictive value of 99%, Figure, B).⁷⁰ Comparing natriuretic peptide levels longitudinally in previously stable patients with preexisting heart failure is logical, although the precise extent of an increase that might be deemed clinically significant has not been established. At present, there are no national guidelines for the diagnosis and management of acute heart failure syndromes in North America.

View larger version (22K): [in this window] [in a new window]   A, Receiver operator characteristic (ROC) curve for B-type natriuretic peptide testing in the diagnosis of heart failure with acute dyspnea. Reprinted from Maisel et al,68 with permission. Copyright © 2002 Massachusetts Medical Society. All rights reserved. B, Receiver operator characteristic (ROC) curve for aminoterminal proB-type natriuretic peptide testing in the diagnosis of heart failure with acute dyspnea. Reprinted from Januzzi et al,70 with permission. Copyright © 2006 Elsevier.

There has been some skepticism regarding the clinical indications for routine use of blood natriuretic peptide testing in the initial evaluation of patients presenting with signs and symptoms heart failure, particularly in the non-acute setting.⁷¹ Moreover, a single-point measurement of blood natriuretic peptide with levels between 80 and 300 pg/mL using the Biosite assay has been reported to be less reliable in the setting of acute heart failure with "flash" pulmonary edema as the level of blood BNP or NT-proBNP may not have had sufficient time to rise.⁷² These natriuretic peptide "grayzones" in the diagnosis of heart failure may also be influenced by the presence of underlying history of heart failure, where the "dry" blood natriuretic peptide level may fall within this range.^55,73,74 There are also challenges with the specific "cut-offs" in certain populations such as in the elderly.⁷⁵ Furthermore, absolute values as well as changes in blood natriuretic peptide levels may correlate with clinical or echocardiographic parameters, but such correlations may vary considerably. There have been reports illustrating the lack of a tight relationship between blood natriuretic peptide levels and blood volume assessment,⁷⁶ left ventricular ejection fraction,⁶⁰ and hemodynamic parameters.^77–79 Therefore, at this time, natriuretic peptide testing should still be considered only as part of the diagnostic evaluation in heart failure, and not the diagnostic definition.

2. BNP or NT-proBNP for Confirmation of the Heart Failure Diagnosis
There is a consensus among the latest American College of Cardiology (ACC)/American Heart Association (AHA), Heart Failure Society of America (HFSA), and other guidelines regarding the management of chronic heart failure that blood natriuretic peptide testing should be performed to confirm the diagnosis of heart failure among patients with suspected diagnosis of heart failure, but only in those who present with signs and symptoms that are ambiguous or which occur in the setting of confounding disease states (such as chronic obstructive pulmonary diseases⁸⁰). Such levels can be valuable to improve the diagnostic accuracy for detecting heart failure. Furthermore, blood natriuretic peptide testing has found to be useful in differentiating different mechanisms of cardiac dysfunction (restrictive cardiomyopathy versus constrictive cardiomyopathy⁸¹), and in identifying cardiac involvement in systemic diseases.^82,83

Careful prospective evaluation of the utility of blood natriuretic peptide testing has not been conducted in the non-acute ambulatory care setting. By deduction, the clinical utility of natriuretic peptide testing in confirming the diagnosis of heart failure in symptomatic patients in the ambulatory care setting should be comparable to the acute setting, where more of the existing data regarding natriuretic peptide testing are derived from. It is important to point out that among minimally or chronically symptomatic patients in the non-acute, ambulatory care setting, blood natriuretic peptide levels may vary, and the diagnostic ranges may be different from that in the acute setting (see Section III on "Screening"). Hence, the cut-off values used in the acute setting may not reliably translate into the ambulatory care setting among patients with chronic stable heart failure. There also have been reports that in the ambulatory care setting, patients with stable but symptomatic chronic heart failure can have blood natriuretic peptide levels that are relatively lower than would normally considered to be "diagnostic" of heart failure (eg, Biosite BNP <100 pg/mL).⁵⁹ This is in direct contrast to the over 90% of patients presenting with blood BNP levels >100 pg/mL in the acute care setting.⁸⁴ Nevertheless, this cut-off is still likely to be helpful in excluding a diagnosis of heart failure when verified by a careful history and physical examination.

B. Risk Stratification of Heart Failure
Recommendations for Use of Biochemical Markers for Risk Stratification of Heart Failure

Class IIa

1. Blood BNP or NT-proBNP testing can provide a useful addition to clinical assessment in selected situations when additional risk stratification is required. (Level of Evidence: A)
   
2. Serial blood BNP or NT-proBNP concentrations may be used to track changes in risk profiles and clinical status among patients with heart failure in selected situations where additional risk stratification is required. (Level of Evidence: B)
   

Class IIb

1. Cardiac troponin testing can identify patients with heart failure at increased risk beyond the setting of acute coronary syndromes. (Level of Evidence: B)
   

Class III

1. Routine blood biomarker testing for the sole purpose of risk stratification in patients with heart failure is not warranted. (Level of Evidence: B)
   

1. Risk stratification of Patients With and Without Heart Failure Using BNP or NT-proBNP
There is a growing body of consistent literature supporting the utility of blood natriuretic peptide testing for risk stratification among patients with heart failure, or even those without prior history of heart failure.⁸⁵ This applies to a wide variety of clinical settings, including acute coronary syndromes,^86–89 stable coronary artery disease,^90–92 decompensated heart failure,^93,94 stable chronic heart failure,⁹⁵ and even non-cardiac disorders such as pulmonary embolism^96,97 or in the general population with no prior history of heart failure⁸⁵ or those at risk of developing heart failure.⁹⁸ There have also been studies advocating the role of blood natriuretic peptide testing in selection for cardiac transplantation,^8,99,100 as well as implantation of cardiac defibrillators¹⁰¹ or cardiac resynchronization therapy.^102–104 Furthermore, blood natriuretic peptide levels have been found to be an important independent predictor of sudden death¹⁰⁵ and equivalent in risk stratification to the Heart Failure Survival Score.¹⁰⁶ Natriuretic peptides also provide incremental prognostic value with standard clinical and laboratory prognostic indicators.^98,107

It is important to also point out that changes in blood natriuretic peptide levels have been associated with differences in long-term clinical outcomes (see Section IV on "Guiding Management"). In addition, it is also worthwhile to recognize that the absolute values of the ranges in different risk strata reported in the literature vary considerably, depending on the patient population. Indeed, even when the blood natriuretic peptide levels were intermediate in the diagnosis of heart failure, their long-term prognostic values remained robust.^74,108 However, the prognostic value of natriuretic peptide testing is still limited by a lack of clear utility in guiding clinical management. The challenge is to better define the specific situations in which risk stratification can be clinically beneficial, and what is deemed to be "false-positive" or "false-negative" may reveal underlying pathophysiologic manifestations that are still not clinically apparent.¹⁰⁹

Current medical management of patients with heart failure relies on patients’ and physicians’ subjective clinical assessment and various non-specific laboratory measurements of organ dysfunction and fluid status. Blood natriuretic peptide levels fall rapidly following diuretic therapy in patients with decompensated heart failure,^131–133 although these changes may vary widely and can be independent of hemodynamic changes.⁷⁷ Furthermore, blood natriuretic peptides may correlate with symptom status in the outpatient setting.¹³⁴ The intra-individual variability of serial natriuretic peptide levels remains highly debated.^135–137 Recent literature from patient cohorts with chronic heart failure¹³⁸ and with acute coronary syndromes¹³⁹ have further illustrated that reduction in blood natriuretic peptide levels over time may be directly associated with corresponding reductions in long-term clinical events. Therefore, serial blood BNP or NT-proBNP concentrations may be used to track changes in risk profiles and clinical status among patients with heart failure in selected situations where additional risk stratification is required.

2. Risk Stratification of Patients With Heart Failure Using Cardiac Troponin
Detectable serum levels of cardiac troponin represent evidence of myocardial necrosis, and have been extensively used in the setting of acute coronary syndromes (ACS). In patients presenting with acute heart failure, cardiac troponin testing has been used as part of the clinical work-up in the acute setting to rule out myocardial ischemia as the primary etiology (refer to Chapter 1 for recommendations). However, in the setting of advanced heart failure^8,110 or in decompensated states,^111–113 some patients may present with transient or persistent elevation of serum cardiac troponin I or troponin T levels in the absence of any obvious myocardial ischemia. Elevated serum troponin levels have been associated with poor long-term prognosis. Several clinical series have further illustrated a strong adverse prognostic effect of sustained elevation of serial serum troponin levels, which may indicate ongoing myocardial damage.^114,115 However, the utility of routine assessment of serum troponin levels in patients with acute or chronic heart failure, as well as the appropriate diagnostic and therapeutic approaches to elevated serum troponin levels in non-ACS setting remains to be determined. This is in part due to the lack of understanding as to whether cardiac troponin levels as markers of myocyte necrosis represents a risk marker versus a risk factor.

	III. Use of Biochemical Markers in Screening for Cardiac Dysfunction

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 
Recommendations for Use of BNP and NT-proBNP in Screening of Heart Failure

Class IIb

1. Blood BNP or NT-proBNP testing can be helpful to identify selected patients with left ventricular systolic dysfunction in the post-infarction setting or to identify patients at high risk of developing heart failure (eg, history of myocardial infarction, diabetes mellitus). However, the diagnostic ranges and cost-effectiveness in different populations remain controversial. (Level of Evidence: B)
   

Class III

1. Routine blood natriuretic peptide (BNP or NT-proBNP) testing is not recommended for screening large asymptomatic patient populations for left ventricular dysfunction. (Level of Evidence: B)
   

A. BNP or NT-proBNP for Screening Heart Failure and Dysfunction
The diagnostic utility of blood natriuretic peptide levels in the acute heart failure setting has prompted interest in evaluation of these biomarkers as screening tools for patients with underlying cardiac dysfunction but no overt signs and symptoms – so-called "asymptomatic left ventricular dysfunction" (ALVD). According to the latest ACC/AHA guidelines for the management of chronic heart failure, a large majority of patients who develop heart failure may have preceding structural cardiac abnormalities ("Stage B heart failure") that can be recognized before disease progression.¹¹⁶ Recent data from the general population from Olmsted County suggest that the prevalence of underlying cardiac structural abnormalities (including ALVD, diastolic dysfunction, valvular abnormalities, left ventricular hypertrophy, and regional wall motion abnormalities) was the highest among individuals within the highest tertile of both BNP and NT-proBNP. Higher NT-proBNP levels have also been associated with greater likelihood of detecting incident heart failure in a population with stable coronary artery disease.¹¹⁷ However, there have been inconclusive data regarding the role of screening for ALVD using natriuretic peptide testing in several studies.^85,118,119 In general, the diagnostic accuracies are far lower compared with the detection of clinical heart failure, which is likely due to the relatively non-specific association with ALVD at ranges of blood natriuretic peptide levels observed in the general population.^120,121

B. Approaches for Screening for Cardiac Dysfunction
There are two approaches to use of natriuretic peptide testing for screening purposes. In the first approach, blood natriuretic peptide testing may be useful in the setting of acute myocardial infarction in the absence of overt heart failure. In this setting, blood natriuretic peptide levels have been inversely associated with post-infarction left ventricular ejection fraction. However, due to the heterogeneity of study populations and the timing of sampling, the accuracy of natriuretic peptide screening has been variable. Echocardiography is likely to remain the main method of assessing LV structural and functional abnormalities after a myocardial infarction.

The second approach is to combine natriuretic peptide testing with other screening modalities to increase the diagnostic accuracy of any single test. This "multi-marker" approach has been broadly studied for risk stratification in the setting of acute coronary syndromes. In this context, combining natriuretic peptide testing with myeloperoxidase or electrocardiography appeared to be promising,^122,123 but further studies are needed to better define these approaches. At this time, most guidelines do not support routine blood natriuretic peptide testing for screening large asymptomatic patient populations for left ventricular systolic dysfunction.

Some investigators have attempted to increase the yield to detect asymptomatic cardiac dysfunction by focusing on high-risk subgroups, a strategy that may be more cost-effective.¹²⁴ A high prevalence of elevated blood natriuretic peptide levels has been observed in a patient population at risk of developing heart failure ("Stage A heart failure"), particularly among those with a history of long-term hypertension, diabetes mellitus,^125,126 coronary artery disease,^92,127 and in the elderly.^128–130 It is conceivable that blood natriuretic peptide testing may be useful for screening these high-risk populations who may otherwise be referred for further echocardiographic screening for ALVD, although the "cut-off" levels may differ in different patient populations. Others have combined several cardiac biomarkers to increase the specificity of screening using inflammatory markers such as MPO or hsCRP.¹²² Until prospective studies are conducted to establish evidence for stratifying patients according to natriuretic peptide levels or to validate a multimarker approach with clinically available assays with cost-effectiveness justifications, broad clinical application of these approaches are still not warranted.

	IV. Use of Biochemical Markers in Guiding Management of Heart Failure

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 
Recommendations for Use of Biochemical Markers in Guiding Management of Heart Failure Patients

Class III

1. Routine blood BNP or NT-proBNP testing is not warranted for making specific therapeutic decisions for patients with acute or chronic heart failure because of the still emerging but incomplete data as well as intra- and inter-individual variations. (Level of Evidence: B)
   

A. Monitoring Therapy Using BNP or NT-proBNP Guidance
The natural extension in natriuretic peptide testing beyond its diagnostic capabilities is to guide therapy in an objective manner. Indeed, this hypothesis has been tested in a small pilot study among patients with mild-to-moderate chronic heart failure. In this study ACE inhibitors and diuretic therapy were titrated to achieve a blood NT-proBNP level of <200 pmol/L by the Christchurch assay (equivalent to 1,680 pg/mL) without compromising other organ function (eg, hypotension, renal insufficiency).¹⁴⁰ This study found significantly fewer total cardiovascular events (deaths, hospital admissions, or episodes of decompensated heart failure based on modified Framingham criteria) in the group randomized to NT-proBNP-guided therapy. These results have been confirmed in a multicenter French study that indicated significant improvement in clinical events following a natriuretic peptide-guided approach compared with standard clinical assessment.¹⁴¹ However, neutral results were also observed when a natriuretic peptide-guided approach was compared with standard clinical assessment.^142,143 Therefore, the concept of natriuretic peptide-guided management of heart failure is still being debated, and there is no general consensus in expert opinion regarding this issue.

Another potential use of blood natriuretic peptide testing in treatment monitoring is the assessment of adequacy of therapy in decompensated heart failure. Pre-discharge, but not initial blood natriuretic peptide levels have consistently been more strongly associated with post-discharge outcomes,^93,144 although the ranges of the changes in blood natriuretic peptides following therapeutic interventions also vary widely. However, the difficulty remains the determination of the "dry" natriuretic peptide levels, which is different from patient to patient. Over-aggressive diuresis based solely on blood natriuretic peptide levels may increase the risk of renal azotemia or extend length of stay without reducing morbidity and mortality.

Several problems have also emerged regarding the clinical feasibility of a natriuretic peptide-guided therapeutic strategy. The wide variation of single or sequential blood natriuretic peptide levels in chronic heart failure after long-term medical therapy have created difficulties in establishing a single "target" level.^{59,60,136,145,146} The frequency of natriuretic peptide testing and the utility of natriuretic peptide testing in monitoring patients with heart failure remain to be determined.

The ability to guide therapeutic decisions using a biomarker-guided approach is highly promising. Several prospective studies are currently underway to confirm the utility of a natriuretic peptide-guided therapeutic strategy.^147,148 However, until these results are available, all clinical guidelines agreed that routine blood BNP or NT-proBNP testing is still not warranted for therapeutic decisions for patients with acute or chronic heart failure, primarily due to the mixed results from clinical studies and inter- and intra-individual as well as inter-assay variabilities.

	Footnotes

 
This article has been copublished simultaneously online with the journal Clinical Biochemistry and at www.aacc.org.

All relationships with industry for the writing group members are reported online at http://www.aacc.org/AACC/members/nacb/LMPG/OnlineGuide/ PublishedGuidelines/ACSHeart/heartpdf.htm.

The materials in this publication represent the opinions of the authors and committee members, and do not represent the official position of the National Academy of Clinical Biochemistry (NACB). The National Academy of Clinical Biochemistry is the academy of the American Association for Clinical Chemistry.

	References

Top Introduction I. Overview of Heart... II. Use of Biochemical... III. Use of Biochemical... IV. Use of Biochemical... References

 
1. Mueller C, Scholer A, Laule-Kilian K, Martina B, Schindler C, Buser P, Pfisterer M, Perruchoud AP. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med. 2004; 350: 647–654.[Abstract/Free Full Text]

2. Mueller C, Laule-Kilian K, Schindler C, Klima T, Frana B, Rodriguez D, Scholer A, Christ M, Perruchoud AP. Cost-effectiveness of B-type natriuretic peptide testing in patients with acute dyspnea. Arch Intern Med. 2006; 166: 1081–1087.[Abstract/Free Full Text]

3. Hunt SA, Abraham WT, Chin MH, Feldman AM, Francis GS, Ganiats TG, Jessup M, Konstam MA, Mancini DM, Michl K, Oates JA, Rahko PS, Silver MA, Stevenson LW, Yancy CW, Antman EM, Smith SC Jr, Adams CD, Anderson JL, Faxon DP, Fuster V, Halperin JL, Hiratzka LF, Jacobs AK, Nishimura R, Ornato JP, Page RL, Riegel B. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation. 2005; 112: e154–e235.[Free Full Text]

4. Rosamond W, Flegal K, Friday G, Furie K, Go A, Greenlund K, Haase N, Ho M, Howard V, Kissela B, Kittner S, Lloyd-Jones D, McDermott M, Meigs J, Moy C, Nichol G, O’Donnell CJ, Roger V, Rumsfeld J, Sorlie P, Steinberger J, Thom T, Wasserthiel-Smoller S, Hong Y. Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2007; 115: e69–e171.[Free Full Text]

5. Bhalla V, Willis S, Maisel AS. B-type natriuretic peptide: the level and the drug-partners in the diagnosis of congestive heart failure. Congest Heart Fail. 2004; (suppl 1): 3–27.

6. Kalra PR, Clague JR, Bolger AP, Anker SD, Poole-Wilson PA, Struthers AD, Coats AJ. Myocardial production of C-type natriuretic peptide in chronic heart failure. Circulation. 2003; 107: 571–573.[Abstract/Free Full Text]

7. Kinugawa T, Kato M, Ogino K, Osaki S, Igawa O, Hisatome I, Shigemasa C. Plasma endothelin-1 levels and clinical correlates in patients with chronic heart failure. J Card Fail. 2003; 9: 318–324.[CrossRef][Medline] [Order article via Infotrieve]

8. Horwich TB, Patel J, MacLellan WR, Fonarow GC. Cardiac troponin I is associated with impaired hemodynamics, progressive left ventricular dysfunction, and increased mortality rates in advanced heart failure. Circulation. 2003; 108: 833–838.[Abstract/Free Full Text]

9. Berton G, Cordiano R, Palmieri R, Pianca S, Pagliara V, Palatini P. C-reactive protein in acute myocardial infarction: association with heart failure. Am Heart J. 2003; 145: 1094–1101.[CrossRef][Medline] [Order article via Infotrieve]

10. Alonso-Martinez JL, Llorente-Diez B, Echegaray-Agara M, Olaz-Preciado F, Urbieta-Echezarreta M, Gonzalez-Arencibia C. C-reactive protein as a predictor of improvement and readmission in heart failure. Eur J Heart Fail. 2002; 4: 331–336.[CrossRef][Medline] [Order article via Infotrieve]

11. Chen MM, Ashley EA, Deng DX, Tsalenko A, Deng A, Tabibiazar R, Ben-Dor A, Fenster B, Yang E, King JY, Fowler M, Robbins R, Johnson FL, Bruhn L, McDonagh T, Dargie H, Yakhini Z, Tsao PS, Quertermous T. Novel role for the potent endogenous inotrope apelin in human cardiac dysfunction. Circulation. 2003; 108: 1432–1439.[Abstract/Free Full Text]

12. Foldes G, Horkay F, Szokodi I, Vuolteenaho O, Ilves M, Lindstedt KA, Mayranpaa M, Sarman B, Seres L, Skoumal R, Lako-Futo Z, deChatel R, Ruskoaho H, Toth M. Circulating and cardiac levels of apelin, the novel ligand of the orphan receptor APJ, in patients with heart failure. Biochem Biophys Res Commun. 2003; 308: 480–485.[CrossRef][Medline] [Order article via Infotrieve]

13. O’Brien RJ, Loke I, Davies JE, Squire IB, Ng LL. Myotrophin in human heart failure. J Am Coll Cardiol. 2003; 42: 719–725.[Abstract/Free Full Text]

14. Ng LL, Loke I, O’Brien RJ, Squire IB, Davies JE. Plasma urotensin in human systolic heart failure. Circulation. 2002; 106: 2877–2880.[Abstract/Free Full Text]

15. Richards AM, Nicholls MG, Lainchbury JG, Fisher S, Yandle TG. Plasma urotensin II in heart failure. Lancet. 2002; 360: 545–546.[CrossRef][Medline] [Order article via Infotrieve]

16. Douglas SA, Tayara L, Ohlstein EH, Halawa N, Giaid A. Congestive heart failure and expression of myocardial urotensin II. Lancet. 2002; 359: 1990–1997.[CrossRef][Medline] [Order article via Infotrieve]

17. Richards AM, Doughty R, Nicholls MG, MacMahon S, Sharpe N, Murphy J, Espiner EA, Frampton C, Yandle TG. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group. J Am Coll Cardiol. 2001; 37: 1781–1787.[Abstract/Free Full Text]

18. Richards AM, Nicholls MG, Yandle TG, Frampton C, Espiner EA, Turner JG, Buttimore RC, Lainchbury JG, Elliott JM, Ikram H, Crozier IG, Smyth DW. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation. 1998; 97: 1921–1929.[Abstract/Free Full Text]

19. Gegenhuber A, Struck J, Dieplinger B, Poelz W, Pacher R, Morgenthaler NG, Bergmann A, Haltmayer M, Mueller T. Comparative evaluation of B-type natriuretic peptide, mid-regional pro-A-type natriuretic peptide, mid-regional pro-adrenomedullin, and Copeptin to predict 1-year mortality in patients with acute destabilized heart failure. J Card Fail. 2007; 13: 42–49.[CrossRef][Medline] [Order article via Infotrieve]

20. Talwar S, Squire IB, Downie PF, O’Brien RJ, Davies JE, Ng LL. Elevated circulating cardiotrophin-1 in heart failure: relationship with parameters of left ventricular systolic dysfunction. Clin Sci (Lond). 2000; 99: 83–88.[Medline] [Order article via Infotrieve]

21. Ng LL, O’Brien RJ, Demme B, Jennings S. Non-competitive immunochemiluminometric assay for cardiotrophin-1 detects elevated plasma levels in human heart failure. Clin Sci (Lond). 2002; 102: 411–416.[Medline] [Order article via Infotrieve]

22. Ng LL, Loke IW, O’Brien RJ, Squire IB, Davies JE. Plasma urocortin in human systolic heart failure. Clin Sci (Lond). 2004; 106: 383–388.[Medline] [Order article via Infotrieve]

23. Weinberg EO, Shimpo M, Hurwitz S, Tominaga S, Rouleau JL, Lee RT. Identification of serum soluble ST2 receptor as a novel heart failure biomarker. Circulation. 2003; 107: 721–726.[Abstract/Free Full Text]

24. Tang WH, Brennan ML, Philip K, Tong W, Mann S, Van Lente F, Hazen SL. Plasma myeloperoxidase levels in patients with chronic heart failure. Am J Cardiol. 2006; 98: 796–799.[CrossRef][Medline] [Order article via Infotrieve]

25. Stoiser B, Mortl D, Hulsmann M, Berger R, Struck J, Morgenthaler NG, Bergmann A, Pacher R. Copeptin, a fragment of the vasopressin precursor, as a novel predictor of outcome in heart failure. Eur J Clin Invest. 2006; 36: 771–778.[CrossRef][Medline] [Order article via Infotrieve]

26. Kempf T, Horn-Wichmann R, Brabant G, Peter T, Allhoff T, Klein G, Drexler H, Johnston N, Wallentin L, Wollert KC. Circulating concentrations of growth-differentiation factor 15 in apparently healthy elderly individuals and patients with chronic heart failure as assessed by a new immunoradiometric sandwich assay. Clin Chem. 2007; 53: 284–291.[Abstract/Free Full Text]

27. Iaccarino G, Barbato E, Cipolletta E, De Amicis V, Margulies KB, Leosco D, Trimarco B, Koch WJ. Elevated myocardial and lymphocyte GRK2 expression and activity in human heart failure. Eur Heart J. 2005; 26: 1752–1758.[Abstract/Free Full Text]

28. Sharma UC, Pokharel S, van Brakel TJ, van Berlo JH, Cleutjens JP, Schroen B, Andre S, Crijns HJ, Gabius HJ, Maessen J, Pinto YM. Galectin-3 marks activated macrophages in failure-prone hypertrophied hearts and contributes to cardiac dysfunction. Circulation. 2004; 110: 3121–3128.[Abstract/Free Full Text]

29. Liang F, O’Rear J, Schellenberger U, Tai L, Lasecki M, Schreiner GF, Apple FS, Maisel AS, Pollitt NS, Protter AA. Evidence for functional heterogeneity of circulating B-type natriuretic peptide. J Am Coll Cardiol. 2007; 49: 1071–1078.[Abstract/Free Full Text]

30. Richards AM. The natriuretic peptides in heart failure. Basic Res Cardiol. 2004; 99: 94–100.[CrossRef][Medline] [Order article via Infotrieve]

31. Murdoch DR, McDonagh TA, Byrne J, Blue L, Farmer R, Morton JJ, Dargie HJ. Titration of vasodilator therapy in chronic heart failure according to plasma brain natriuretic peptide concentration: randomized comparison of the hemodynamic and neuroendocrine effects of tailored versus empirical therapy. Am Heart J. 1999; 138: 1126–1132.[CrossRef][Medline] [Order article via Infotrieve]

32. Brunner-La Rocca HP, Weilenmann D, Kiowski W, Maly FE, Candinas R, Follath F. Within-patient comparison of effects of different dosages of enalapril on functional capacity and neurohormone levels in patients with chronic heart failure. Am Heart J. 1999; 138: 654–662.[CrossRef][Medline] [Order article via Infotrieve]

33. Latini R, Masson S, Anand I, Judd D, Maggioni AP, Chiang YT, Bevilacqua M, Salio M, Cardano P, Dunselman PH, Holwerda NJ, Tognoni G, Cohn JN. Effects of valsartan on circulating brain natriuretic peptide and norepinephrine in symptomatic chronic heart failure: the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2002; 106: 2454–2458.[Abstract/Free Full Text]

34. Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, Matsumoto T, Matsui T, Kinoshita M. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001; 37: 1228–1233.[Abstract/Free Full Text]

35. Rousseau MF, Gurne O, Duprez D, Van Mieghem W, Robert A, Ahn S, Galanti L, Ketelslegers JM. Beneficial neurohormonal profile of spironolactone in severe congestive heart failure: results from the RALES neurohormonal substudy. J Am Coll Cardiol. 2002; 40: 1596–1601.[Abstract/Free Full Text]

36. Davis ME, Richards AM, Nicholls MG, Yandle TG, Frampton CM, Troughton RW. Introduction of metoprolol increases plasma B-type cardiac natriuretic peptides in mild, stable heart failure. Circulation. 2006; 113: 977–985.[Abstract/Free Full Text]

37. Maisel AS. The diagnosis of acute congestive heart failure: role of BNP measurements. Heart Fail Rev. 2003; 8: 327–334.[CrossRef][Medline] [Order article via Infotrieve]

38. Januzzi JL, van Kimmenade R, Lainchbury J, Bayes-Genis A, Ordonez-Llanos J, Santalo-Bel M, Pinto YM, Richards M. NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J. 2006; 27: 330–337.[Abstract/Free Full Text]

39. Redfield MM, Rodeheffer RJ, Jacobsen SJ, Mahoney DW, Bailey KR, Burnett JC, Jr. Plasma brain natriuretic peptide concentration: impact of age and gender. J Am Coll Cardiol. 2002; 40: 976–982.[Abstract/Free Full Text]

40. Tetin SY, Ruan Q, Saldana SC, Pope MR, Chen Y, Wu H, Pinkus MS, Jiang J, Richardson PL. Interactions of two monoclonal antibodies with BNP: high resolution epitope mapping using fluorescence correlation spectroscopy. Biochemistry. 2006; 45: 14155–14165.[CrossRef][Medline] [Order article via Infotrieve]

41. Emdin M, Passino C, Del Ry S, Prontera C, Galetta F, Clerico A. Influence of gender on circulating cardiac natriuretic hormones in patients with heart failure. Clin Chem Lab Med. 2003; 41: 686–692.[CrossRef][Medline] [Order article via Infotrieve]

42. Loke I, Squire IB, Davies JE, Ng LL. Reference ranges for natriuretic peptides for diagnostic use are dependent on age, gender and heart rate. Eur J Heart Fail. 2003; 5: 599–606.[CrossRef][Medline] [Order article via Infotrieve]

43. McLean AS, Huang SJ, Nalos M, Tang B, Stewart DE. The confounding effects of age, gender, serum creatinine, and electrolyte concentrations on plasma B-type natriuretic peptide concentrations in critically ill patients. Crit Care Med. 2003; 31: 2611–2618.[CrossRef][Medline] [Order article via Infotrieve]

44. McCullough PA, Duc P, Omland T, McCord J, Nowak RM, Hollander JE, Herrmann HC, Steg PG, Westheim A, Knudsen CW, Storrow AB, Abraham WT, Lamba S, Wu AH, Perez A, Clopton P, Krishnaswamy P, Kazanegra R, Maisel AS. B-type natriuretic peptide and renal function in the diagnosis of heart failure: an analysis from the Breathing Not Properly Multinational Study. Am J Kidney Dis. 2003; 41: 571–579.[CrossRef][Medline] [Order article via Infotrieve]

45. Vesely DL. Natriuretic peptides and acute renal failure. Am J Physiol Renal Physiol. 2003; 285: F167–F177.[Abstract/Free Full Text]

46. McCollough PA, Kuncheria J, Mathur VS. Diagnostic and therapeutic utility of B-type natriuretic peptide in patients with renal insufficiency and decompensated heart failure. Rev Cardiovasc Med. 2003; 4 (suppl 7): S3–S12.

47. Herrmann Z, Uhl W, Steinberg HW, Dworschack R. The influence of renal function on NT-proBNP levels in various disease groups. Clin Lab. 2003; 49: 649–656.[Medline] [Order article via Infotrieve]

48. Anwaruddin S, Lloyd-Jones DM, Baggish A, Chen A, Krauser D, Tung R, Chae C, Januzzi JL Jr. Renal function, congestive heart failure, and amino-terminal pro-brain natriuretic peptide measurement: results from the ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study. J Am Coll Cardiol. 2006; 47: 91–97.[Abstract/Free Full Text]

49. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Wilson PW, Vasan RS. Impact of obesity on plasma natriuretic peptide levels. Circulation. 2004; 109: 594–600.[Abstract/Free Full Text]

50. Taylor JA, Christenson RH, Rao K, Jorge M, Gottlieb SS. B-type natriuretic peptide and N-terminal pro B-type natriuretic peptide are depressed in obesity despite higher left ventricular end diastolic pressures. Am Heart J. 2006; 152: 1071–1076.[CrossRef][Medline] [Order article via Infotrieve]

51. Krauser DG, Lloyd-Jones DM, Chae CU, Cameron R, Anwaruddin S, Baggish AL, Chen A, Tung R, Januzzi JL Jr. Effect of body mass index on natriuretic peptide levels in patients with acute congestive heart failure: a ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) substudy. Am Heart J. 2005; 149: 744–750.[CrossRef][Medline] [Order article via Infotrieve]

52. Schultz M, Faber J, Kistorp C, Jarlov A, Pedersen F, Wiinberg N, Hildebrandt P. N-terminal-pro-B-type natriuretic peptide (NT-pro-BNP) in different thyroid function states. Clin Endocrinol (Oxf). 2004; 60: 54–59.[CrossRef][Medline] [Order article via Infotrieve]

53. Missouris CG, Grouzmann E, Buckley MG, Barron J, MacGregor GA, Singer DR. How does treatment influence endocrine mechanisms in acute severe heart failure? Effects on cardiac natriuretic peptides, the renin system, neuropeptide Y and catecholamines. Clin Sci (Lond). 1998; 94: 591–599.[Medline] [Order article via Infotrieve]

54. Ralli S, Horwich TB, Fonarow GC. Relationship between anemia, cardiac troponin I, and B-type natriuretic peptide levels and mortality in patients with advanced heart failure. Am Heart J. 2005; 150: 1220–1227.[CrossRef][Medline] [Order article via Infotrieve]

55. Chung T, Sindone A, Foo F, Dwyer A, Paoloni R, Janu MR, Wong H, Hall J, Freedman SB. Influence of history of heart failure on diagnostic performance and utility of B-type natriuretic peptide testing for acute dyspnea in the emergency department. Am Heart J. 2006; 152: 949–955.[CrossRef][Medline] [Order article via Infotrieve]

56. Albage A, Kenneback G, van der Linden J, Berglund H. Improved neurohormonal markers of ventricular function after restoring sinus rhythm by the Maze procedure. Ann Thorac Surg. 2003; 75: 790–795.[Abstract/Free Full Text]

57. Inoue S, Murakami Y, Sano K, Katoh H, Shimada T. Atrium as a source of brain natriuretic polypeptide in patients with atrial fibrillation. J Card Fail. 2000; 6: 92–96.[Medline] [Order article via Infotrieve]

58. Rossi A, Enriquez-Sarano M, Burnett JC, Jr., Lerman A, Abel MD, Seward JB. Natriuretic peptide levels in atrial fibrillation: a prospective hormonal and Doppler-echocardiographic study. J Am Coll Cardiol. 2000; 35: 1256–1262.[Abstract/Free Full Text]

59. Tang WH, Girod JP, Lee MJ, Starling RC, Young JB, Van Lente F, Francis GS. Plasma B-type natriuretic peptide levels in ambulatory patients with established chronic symptomatic systolic heart failure. Circulation. 2003; 108: 2964–2966.[Abstract/Free Full Text]

60. Troughton RW, Prior DL, Pereira JJ, Martin M, Fogarty A, Morehead A, Yandle TG, Richards AM, Starling RC, Young JB, Thomas JD, Klein AL. Plasma B-type natriuretic peptide levels in systolic heart failure: importance of left ventricular diastolic function and right ventricular systolic function. J Am Coll Cardiol. 2004; 43: 416–422.[Abstract/Free Full Text]

61. Lubien E, DeMaria A, Krishnaswamy P, Clopton P, Koon J, Kazanegra R, Gardetto N, Wanner E, Maisel AS. Utility of B-natriuretic peptide in detecting diastolic dysfunction: comparison with Doppler velocity recordings. Circulation. 2002; 105: 595–601.[Abstract/Free Full Text]

62. Maisel AS, McCord J, Nowak RM, Hollander JE, Wu AH, Duc P, Omland T, Storrow AB, Krishnaswamy P, Abraham WT, Clopton P, Steg G, Aumont MC, Westheim A, Knudsen CW, Perez A, Kamin R, Kazanegra R, Herrmann HC, McCullough PA. Bedside B-Type natriuretic peptide in the emergency diagnosis of heart failure with reduced or preserved ejection fraction. Results from the Breathing Not Properly Multinational Study. J Am Coll Cardiol. 2003; 41: 2010–2017.[Abstract/Free Full Text]

63. Cheung BM. Plasma concentration of brain natriuretic peptide is related to diastolic function in hypertension. Clin Exp Pharmacol Physiol. 1997; 24: 966–968.[Medline] [Order article via Infotrieve]

64. Masson S, Vago T, Baldi G, Salio M, De Angelis N, Nicolis E, Maggioni AP, Latini R, Norbiato G, Bevilacqua M. Comparative measurement of N-terminal pro-brain natriuretic peptide and brain natriuretic peptide in ambulatory patients with heart failure. Clin Chem Lab Med. 2002; 40: 761–763.[CrossRef][Medline] [Order article via Infotrieve]

65. Yeo KT, Wu AH, Apple FS, Kroll MH, Christenson RH, Lewandrowski KB, Sedor FA, Butch AW. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta. 2003; 338: 107–115.[CrossRef][Medline] [Order article via Infotrieve]

66. Wu AH, Smith A, Wieczorek S, Mather JF, Duncan B, White CM, McGill C, Katten D, Heller G. Biological variation for N-terminal pro- and B-type natriuretic peptides and implications for therapeutic monitoring of patients with congestive heart failure. Am J Cardiol. 2003; 92: 628–631.[CrossRef][Medline] [Order article via Infotrieve]

67. Wang TJ, Larson MG, Levy D, Benjamin EJ, Corey D, Leip EP, Vasan RS. Heritability and genetic linkage of plasma natriuretic peptide levels. Circulation. 2003; 108: 13–16.[Abstract/Free Full Text]

68. Maisel AS, Krishnaswamy P, Nowak RM, McCord J, Hollander JE, Duc P, Omland T, Storrow AB, Abraham WT, Wu AH, Clopton P, Steg PG, Westheim A, Knudsen CW, Perez A, Kazanegra R, Herrmann HC, McCullough PA. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med. 2002; 347: 161–167.[Abstract/Free Full Text]

69. Wright SP, Doughty RN, Pearl A, Gamble GD, Whalley GA, Walsh HJ, Gordon G, Bagg W, Oxenham H, Yandle T, Richards M, Sharpe N. Plasma amino-terminal pro-brain natriuretic peptide and accuracy of heart-failure diagnosis in primary care: a randomized, controlled trial. J Am Coll Cardiol. 2003; 42: 1793–1800.[Abstract/Free Full Text]

70. Januzzi JL, Jr., Camargo CA, Anwaruddin S, Baggish AL, Chen AA, Krauser DG, Tung R, Cameron R, Nagurney JT, Chae CU, Lloyd-Jones DM, Brown DF, Foran-Melanson S, Sluss PM, Lee-Lewandrowski E, Lewandrowski KB. The N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study. Am J Cardiol. 2005; 95: 948–954.[CrossRef][Medline] [Order article via Infotrieve]

71. Packer M. Should B-type natriuretic peptide be measured routinely to guide the diagnosis and management of chronic heart failure? Circulation. 2003; 108: 2950–2953.[Free Full Text]

72. Logeart D, Saudubray C, Beyne P, Thabut G, Ennezat PV, Chavelas C, Zanker C, Bouvier E, Solal AC. Comparative value of Doppler echocardiography and B-type natriuretic peptide assay in the etiologic diagnosis of acute dyspnea. J Am Coll Cardiol. 2002; 40: 1794–1800.[Abstract/Free Full Text]

73. Coste J, Jourdain P, Pouchot J. A gray zone assigned to inconclusive results of quantitative diagnostic tests: application to the use of brain natriuretic Peptide for diagnosis of heart failure in acute dyspneic patients. Clin Chem. 2006; 52: 2229–2235.[Abstract/Free Full Text]

74. Brenden CK, Hollander JE, Guss D, McCullough PA, Nowak R, Green G, Saltzberg M, Ellison SR, Bhalla MA, Bhalla V, Clopton P, Jesse R, Maisel AS. Gray zone BNP levels in heart failure patients in the emergency department: results from the Rapid Emergency Department Heart Failure Outpatient Trial (REDHOT) multicenter study. Am Heart J. 2006; 151: 1006–1011.[CrossRef][Medline] [Order article via Infotrieve]

75. Berdague P, Caffin PY, Barazer I, Vergnes C, Sedighian S, Letrillard S, Pilossof R, Goutorbe F, Piot C, Reny JL. Use of N-terminal prohormone brain natriuretic peptide assay for etiologic diagnosis of acute dyspnea in elderly patients. Am Heart J. 2006; 151: 690–698.[CrossRef][Medline] [Order article via Infotrieve]

76. James KB, Troughton RW, Feldschuh J, Soltis D, Thomas D, Fouad-Tarazi F. Blood volume and brain natriuretic peptide in congestive heart failure: a pilot study. Am Heart J. 2005; 150: 984.[CrossRef][Medline] [Order article via Infotrieve]

77. O’Neill JO, Bott-Silverman CE, McRae AT 3rd, Troughton RW, Ng K, Starling RC, Young JB. B-type natriuretic peptide levels are not a surrogate marker for invasive hemodynamics during management of patients with severe heart failure. Am Heart J. 2005; 149: 363–269.[CrossRef][Medline] [Order article via Infotrieve]

78. Dokainish H, Zoghbi WA, Lakkis NM, Al-Bakshy F, Dhir M, Quinones MA, Nagueh SF. Optimal noninvasive assessment of left ventricular filling pressures: a comparison of tissue Doppler echocardiography and B-type natriuretic peptide in patients with pulmonary artery catheters. Circulation. 2004; 109: 2432–2439.[Abstract/Free Full Text]

79. Cioffi G, Tarantini L, Stefenelli C, Azzetti G, Marco R, Carlucci S, Furlanello F. Changes in plasma N-terminal proBNP levels and ventricular filling pressures during intensive unloading therapy in elderly with decompensated congestive heart failure and preserved left ventricular systolic function. J Card Fail. 2006; 12: 608–615.[CrossRef][Medline] [Order article via Infotrieve]

80. Le Jemtel TH, Padeletti M, Jelic S. Diagnostic and therapeutic challenges in patients with coexistent chronic obstructive pulmonary disease and chronic heart failure. J Am Coll Cardiol. 2007; 49: 171–180.[Abstract/Free Full Text]

81. Leya FS, Arab D, Joyal D, Shioura KM, Lewis BE, Steen LH, Cho L. The efficacy of brain natriuretic peptide levels in differentiating constrictive pericarditis from restrictive cardiomyopathy. J Am Coll Cardiol. 2005; 45: 1900–1902.[Abstract/Free Full Text]

82. McKie PM, Rodeheffer RJ, Cataliotti A, Martin FL, Urban LH, Mahoney DW, Jacobsen SJ, Redfield MM, Burnett JC Jr. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide: biomarkers for mortality in a large community-based cohort free of heart failure. Hypertension. 2006; 47: 874–880.[Abstract/Free Full Text]

83. Karadag O, Calguneri M, Yavuz B, Atalar E, Akdogan A, Kalyoncu U, Kiraz S, Aksoyek S, Ozmen F, Ertenli AI. B-type natriuretic peptide (BNP) levels in female systemic lupus erythematosus patients: what is the clinical significance? Clin Rheumatol. February 21, 2007. DOI: 10.1007/s10067-007-0575-4. Available at: http://www.springerlink.com/content/ku96x425v676345t/.

84. Hogenhuis J, Voors AA, Jaarsma T, Hillege HL, Hoes AW, van Veldhuisen DJ. Low prevalence of B-type natriuretic peptide levels < 100 pg/mL in patients with heart failure at hospital discharge. Am Heart J. 2006; 151: 1012.e1–5.

85. Wang TJ, Larson MG, Levy D, Benjamin EJ, Leip EP, Omland T, Wolf PA, Vasan RS. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med. 2004; 350: 655–663.[Abstract/Free Full Text]

86. James SK, Lindahl B, Siegbahn A, Stridsberg M, Venge P, Armstrong P, Barnathan ES, Califf R, Topol EJ, Simoons ML, Wallentin L. N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy. Circulation. 2003; 108: 275–281.[Abstract/Free Full Text]

87. Richards AM, Nicholls MG, Espiner EA, Lainchbury JG, Troughton RW, Elliott J, Frampton C, Turner J, Crozier IG, Yandle TG. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation. 2003; 107: 2786–2792.[Abstract/Free Full Text]

88. Omland T, Persson A, Ng L, O’Brien R, Karlsson T, Herlitz J, Hartford M, Caidahl K. N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes. Circulation. 2002; 106: 2913–2918.[Abstract/Free Full Text]

89. de Lemos JA, Morrow DA. Combining natriuretic peptides and necrosis markers in the assessment of acute coronary syndromes. Rev Cardiovasc Med. 2003; 4 (suppl 4): S37–S46.

90. Kragelund C, Gronning B, Kober L, Hildebrandt P, Steffensen R. N-terminal pro-B-type natriuretic peptide and long-term mortality in stable coronary heart disease. N Engl J Med. 2005; 352: 666–675.[Abstract/Free Full Text]

91. Poge U, Gerhardt TM, Woitas RP. N-terminal pro-B-type natriuretic peptide and mortality in coronary heart disease. N Engl J Med. 2005; 352: 2025–2026.[Free Full Text]

92. Richards M, Nicholls MG, Espiner EA, Lainchbury JG, Troughton RW, Elliott J, Frampton CM, Crozier IG, Yandle TG, Doughty R, MacMahon S, Sharpe N. Comparison of B-type natriuretic peptides for assessment of cardiac function and prognosis in stable ischemic heart disease. J Am Coll Cardiol. 2006; 47: 52–60.[Abstract/Free Full Text]

93. Cheng V, Kazanagra R, Garcia A, Lenert L, Krishnaswamy P, Gardetto N, Clopton P, Maisel A. A rapid bedside test for B-type peptide predicts treatment outcomes in patients admitted for decompensated heart failure: a pilot study. J Am Coll Cardiol. 2001; 37: 386–391.[Abstract/Free Full Text]

94. Januzzi JL Jr, Sakhuja R, O’Donoghue M, Baggish AL, Anwaruddin S, Chae CU, Cameron R, Krauser DG, Tung R, Camargo CA Jr, Lloyd-Jones DM. Utility of amino-terminal pro-brain natriuretic peptide testing for prediction of 1-year mortality in patients with dyspnea treated in the emergency department. Arch Intern Med. 2006; 166: 315–320.[Abstract/Free Full Text]

95. Anand IS, Fisher LD, Chiang YT, Latini R, Masson S, Maggioni AP, Glazer RD, Tognoni G, Cohn JN. Changes in brain natriuretic peptide and norepinephrine over time and mortality and morbidity in the Valsartan Heart Failure Trial (Val-HeFT). Circulation. 2003; 107: 1278–1283.[Abstract/Free Full Text]

96. Pruszczyk P, Kostrubiec M, Bochowicz A, Styczynski G, Szulc M, Kurzyna M, Fijalkowska A, Kuch-Wocial A, Chlewicka I, Torbicki A. N-terminal pro-brain natriuretic peptide in patients with acute pulmonary embolism. Eur Respir J. 2003; 22: 649–653.[Abstract/Free Full Text]

97. Kruger S, Graf J, Merx MW, Koch KC, Kunz D, Hanrath P, Janssens U. Brain natriuretic peptide predicts right heart failure in patients with acute pulmonary embolism. Am Heart J. 2004; 147: 60–65.[CrossRef][Medline] [Order article via Infotrieve]

98. Blankenberg S, McQueen MJ, Smieja M, Pogue J, Balion C, Lonn E, Rupprecht HJ, Bickel C, Tiret L, Cambien F, Gerstein H, Munzel T, Yusuf S. Comparative impact of multiple biomarkers and N-Terminal pro-brain natriuretic peptide in the context of conventional risk factors for the prediction of recurrent cardiovascular events in the Heart Outcomes Prevention Evaluation (HOPE) Study. Circulation. 2006; 114: 201–208.[Abstract/Free Full Text]

99. Gardner RS, Ozalp F, Murday AJ, Robb SD, McDonagh TA. N-terminal pro-brain natriuretic peptide. A new gold standard in predicting mortality in patients with advanced heart failure. Eur Heart J. 2003; 24: 1735–1743.[Abstract/Free Full Text]

100. Koglin J, Pehlivanli S, Schwaiblmair M, Vogeser M, Cremer P, Von Scheidt W. Clinical value of brain natriuretic peptide for candidate selection before cardiac transplantation. J Heart Lung Transplant. 2001; 20: 164.[Medline] [Order article via Infotrieve]

101. Verma A, Kilicaslan F, Martin DO, Minor S, Starling R, Marrouche NF, Almahammed S, Wazni OM, Duggal S, Zuzek R, Yamaji H, Cummings J, Chung MK, Tchou PJ, Natale A. Preimplantation B-type natriuretic peptide concentration is an independent predictor of future appropriate implantable defibrillator therapies. Heart. 2006; 92: 190–195.[Abstract/Free Full Text]

102. Pitzalis MV, Iacoviello M, Di Serio F, Romito R, Guida P, De Tommasi E, Luzzi G, Anaclerio M, Varraso L, Forleo C, Pansini N. Prognostic value of brain natriuretic peptide in the management of patients receiving cardiac resynchronization therapy. Eur J Heart Fail. 2006; 8: 509–514.[CrossRef][Medline] [Order article via Infotrieve]

103. Yu CM, Fung JW, Zhang Q, Chan CK, Chan I, Chan YS, Kong SL, Sanderson JE, Lam CW. Improvement of serum NT-ProBNP predicts improvement in cardiac function and favorable prognosis after cardiac resynchronization therapy for heart failure. J Card Fail. 2005; 11: S42–S46.[CrossRef][Medline] [Order article via Infotrieve]

104. Sinha AM, Filzmaier K, Breithardt OA, Kunz D, Graf J, Markus KU, Hanrath P, Stellbrink C. Usefulness of brain natriuretic peptide release as a surrogate marker of the efficacy of long-term cardiac resynchronization therapy in patients with heart failure. Am J Cardiol. 2003; 91: 755–758.[CrossRef][Medline] [Order article via Infotrieve]

105. Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation. 2002; 105: 2392–2397.[Abstract/Free Full Text]

106. Koglin J, Pehlivanli S, Schwaiblmair M, Vogeser M, Cremer P, von Scheidt W. Role of brain natriuretic peptide in risk stratification of patients with congestive heart failure. J Am Coll Cardiol. 2001; 38: 1934–1941.[Abstract/Free Full Text]

107. van Kimmenade RR, Januzzi JL Jr, Baggish AL, Lainchbury JG, Bayes-Genis A, Richards AM, Pinto YM. Amino-terminal pro-brain natriuretic peptide, renal function, and outcomes in acute heart failure: redefining the cardiorenal interaction? J Am Coll Cardiol. 2006; 48: 1621–1627.[Abstract/Free Full Text]

108. van Kimmenade RR, Pinto YM, Bayes-Genis A, Lainchbury JG, Richards AM, Januzzi JL Jr. Usefulness of intermediate amino-terminal pro-brain natriuretic peptide concentrations for diagnosis and prognosis of acute heart failure. Am J Cardiol. 2006; 98: 386–390.[CrossRef][Medline] [Order article via Infotrieve]

109. Drazner MH, de Lemos JA. Unexpected BNP levels in patients with advanced heart failure: a tale of caution and promise. Am Heart J. 2005; 149: 187–189.[CrossRef][Medline] [Order article via Infotrieve]

110. Perna ER, Macin SM, Canella JP, Augier N, Stival JL, Cialzeta JR, Pitzus AE, Garcia EH, Obregon R, Brizuela M, Barbagelata A. Ongoing myocardial injury in stable severe heart failure: value of cardiac troponin T monitoring for high-risk patient identification. Circulation. 2004; 110: 2376–2382.[Abstract/Free Full Text]

111. Macin SM, Perna ER, Cimbaro Canella JP, Augier N, Riera Stival JL, Cialzeta J, Pitzus AE, Obregon R, Garcia E, Medina F, Badaracco RJ. Increased levels of cardiac troponin-T in outpatients with heart failure and preserved systolic function are related to adverse clinical findings and outcome. Coron Artery Dis. 2006; 17: 685–691.[CrossRef][Medline] [Order article via Infotrieve]

112. Perna ER, Macin SM, Cimbaro Canella JP, Alvarenga PM, Rios NG, Pantich R, Augier N, Farias EF, Jantus E, Brizuela M, Medina F. Minor myocardial damage detected by troponin T is a powerful predictor of long-term prognosis in patients with acute decompensated heart failure. Int J Cardiol. 2005; 99: 253–261.[CrossRef][Medline] [Order article via Infotrieve]

113. You JJ, Austin PC, Alter DA, Ko DT, Tu JV. Relation between cardiac troponin I and mortality in acute decompensated heart failure. Am Heart J. 2007; 153: 462–470.[CrossRef][Medline] [Order article via Infotrieve]

114. Stanton EB, Hansen MS, Sole MJ, Gawad Y, Packer M, Pitt B, Swedberg K, Rouleau JL. Cardiac troponin I, a possible predictor of survival in patients with stable congestive heart failure. Can J Cardiol. 2005; 21: 39–43.[Medline] [Order article via Infotrieve]

115. Taniguchi R, Sato Y, Nishio Y, Kimura T, Kita T. Measurements of baseline and follow-up concentrations of cardiac troponin-T and brain natriuretic peptide in patients with heart failure from various etiologies. Heart Vessels. 2006; 21: 344–349.[CrossRef][Medline] [Order article via Infotrieve]

116. Goldberg LR, Jessup M. Stage B heart failure: management of asymptomatic left ventricular systolic dysfunction. Circulation. 2006; 113: 2851–2860.[Free Full Text]

117. Bibbins-Domingo K, Gupta R, Na B, Wu AH, Schiller NB, Whooley MA. N-terminal fragment of the prohormone brain-type natriuretic peptide (NT-proBNP), cardiovascular events, and mortality in patients with stable coronary heart disease. JAMA. 2007; 297: 169–176.[Abstract/Free Full Text]

118. Vasan RS, Benjamin EJ, Larson MG, Leip EP, Wang TJ, Wilson PW, Levy D. Plasma natriuretic peptides for community screening for left ventricular hypertrophy and systolic dysfunction: the Framingham heart study. JAMA. 2002; 288: 1252–1259.[Abstract/Free Full Text]

119. Nakamura M, Tanaka F, Yonezawa S, Satou K, Nagano M, Hiramori K. The limited value of plasma B-type natriuretic peptide for screening for left ventricular hypertrophy among hypertensive patients. Am J Hypertens. 2003; 16: 1025–1029.[CrossRef][Medline] [Order article via Infotrieve]

120. Luchner A, Burnett JC Jr, Jougasaki M, Hense HW, Heid IM, Muders F, Riegger GA, Schunkert H. Evaluation of brain natriuretic peptide as marker of left ventricular dysfunction and hypertrophy in the population. J Hypertens. 2000; 18: 1121–1128.[CrossRef][Medline] [Order article via Infotrieve]

121. Costello-Boerrigter LC, Boerrigter G, Redfield MM, Rodeheffer RJ, Urban LH, Mahoney DW, Jacobsen SJ, Heublein DM, Burnett JC Jr. Amino-terminal pro-B-type natriuretic peptide and B-type natriuretic peptide in the general community: determinants and detection of left ventricular dysfunction. J Am Coll Cardiol. 2006; 47: 345–353.[Abstract/Free Full Text]

122. Ng LL, Pathik B, Loke IW, Squire IB, Davies JE. Myeloperoxidase and C-reactive protein augment the specificity of B-type natriuretic peptide in community screening for systolic heart failure. Am Heart J. 2006; 152: 94–101.[CrossRef][Medline] [Order article via Infotrieve]

123. Jeyaseelan S, Goudie BM, Pringle SD, Donnan PT, Sullivan FM, Struthers AD. A critical re-appraisal of different ways of selecting ambulatory patients with suspected heart failure for echocardiography. Eur J Heart Fail. 2007; 9: 55–61.[CrossRef][Medline] [Order article via Infotrieve]

124. Nielsen OW, McDonagh TA, Robb SD, Dargie HJ. Retrospective analysis of the cost-effectiveness of using plasma brain natriuretic peptide in screening for left ventricular systolic dysfunction in the general population. J Am Coll Cardiol. 2003; 41: 113–120.[Abstract/Free Full Text]

125. Epshteyn V, Morrison K, Krishnaswamy P, Kazanegra R, Clopton P, Mudaliar S, Edelman S, Henry R, Maisel A. Utility of B-type natriuretic peptide (BNP) as a screen for left ventricular dysfunction in patients with diabetes. Diabetes Care. 2003; 26: 2081–2087.[Abstract/Free Full Text]

126. Silver MA, Pisano C. High incidence of elevated B-type natriuretic peptide levels and risk factors for heart failure in an unselected at-risk population (stage A): implications for heart failure screening programs. Congest Heart Fail. 2003; 9: 127–132.[Medline] [Order article via Infotrieve]

127. Tang WH, Steinhubl SR, Van Lente F, Brennan D, McErlean E, Maroo A, Francis GS, Topol EJ. Risk stratification for patients undergoing nonurgent percutaneous coronary intervention using N-terminal pro-B-type natriuretic peptide: a Clopidogrel for the Reduction of Events During Observation (CREDO) substudy. Am Heart J. 2007; 153: 36–41.[CrossRef][Medline] [Order article via Infotrieve]

128. Groenning BA, Raymond I, Hildebrandt PR, Nilsson JC, Baumann M, Pedersen F. Diagnostic and prognostic evaluation of left ventricular systolic heart failure by plasma N-terminal pro-brain natriuretic peptide concentrations in a large sample of the general population. Heart. 2004; 90: 297–303.[Abstract/Free Full Text]

129. Alehagen U, Lindstedt G, Eriksson H, Dahlstrom U. Utility of the amino-terminal fragment of pro-brain natriuretic peptide in plasma for the evaluation of cardiac dysfunction in elderly patients in primary health care. Clin Chem. 2003; 49: 1337–1346.[Abstract/Free Full Text]

130. Hutcheon SD, Gillespie ND, Struthers AD, McMurdo ME. B-type natriuretic peptide in the diagnosis of cardiac disease in elderly day hospital patients. Age Ageing. 2002; 31: 295–301.[Abstract/Free Full Text]

131. Richards AM, Crozier IG, Yandle TG, Espiner EA, Ikram H, Nicholls MG. Brain natriuretic factor: regional plasma concentrations and correlations with haemodynamic state in cardiac disease. Br Heart J. 1993; 69: 414–417.[Abstract/Free Full Text]

132. Kazanegra R, Cheng V, Garcia A, Krishnaswamy P, Gardetto N, Clopton P, Maisel A. A rapid test for B-type natriuretic peptide correlates with falling wedge pressures in patients treated for decompensated heart failure: a pilot study. J Card Fail. 2001; 7: 21–29.[CrossRef][Medline] [Order article via Infotrieve]

133. Johnson W, Omland T, Hall C, Lucas C, Myking OL, Collins C, Pfeffer M, Rouleau JL, Stevenson LW. Neurohormonal activation rapidly decreases after intravenous therapy with diuretics and vasodilators for class IV heart failure. J Am Coll Cardiol. 2002; 39: 1623–1629.[Abstract/Free Full Text]

134. Lee SC, Stevens TL, Sandberg SM, Heublein DM, Nelson SM, Jougasaki M, Redfield MM, Burnett JC Jr. The potential of brain natriuretic peptide as a biomarker for New York Heart Association class during the outpatient treatment of heart failure. J Card Fail. 2002; 8: 149–154.[CrossRef][Medline] [Order article via Infotrieve]

135. Schou M, Gustafsson F, Nielsen PH, Madsen LH, Kjaer A, Hildebrandt PR. Unexplained week-to-week variation in BNP and NT-proBNP is low in chronic heart failure patients during steady state. Eur J Heart Fail. 2007; 9: 68–74.[CrossRef][Medline] [Order article via Infotrieve]

136. Wu AH. Serial testing of B-type natriuretic peptide and NTpro-BNP for monitoring therapy of heart failure: the role of biologic variation in the interpretation of results. Am Heart J. 2006; 152: 828–834.[CrossRef][Medline] [Order article via Infotrieve]

137. O’Hanlon R, O’Shea P, Ledwidge M, O’Loughlin C, Lange S, Conlon C, Phelan D, Cunningham S, McDonald K. The biologic variability of B-type natriuretic peptide and N-terminal pro-B-type natriuretic peptide in stable heart failure patients. J Card Fail. 2007; 13: 50–55.[CrossRef][Medline] [Order article via Infotrieve]

138. Lindahl B, Lindback J, Jernberg T, Johnston N, Stridsberg M, Venge P, Wallentin L. Serial analyses of N-terminal pro-B-type natriuretic peptide in patients with non-ST-segment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy. J Am Coll Cardiol. 2005; 45: 533–541.[Abstract/Free Full Text]

139. Morrow DA, de Lemos JA, Blazing MA, Sabatine MS, Murphy SA, Jarolim P, White HD, Fox KA, Califf RM, Braunwald E. Prognostic value of serial B-type natriuretic peptide testing during follow-up of patients with unstable coronary artery disease. JAMA. 2005; 294: 2866–2871.[Abstract/Free Full Text]

140. Troughton RW, Frampton CM, Yandle TG, Espiner EA, Nicholls MG, Richards AM. Treatment of heart failure guided by plasma aminoterminal brain natriuretic peptide (N-BNP) concentrations. Lancet. 2000; 355: 1126–1130.[CrossRef][Medline] [Order article via Infotrieve]

141. Jourdain P, Jondeau G, Funck F, Gueffet P, Le Helloco A, Donal E, Aupetit JF, Aumont MC, Galinier M, Eicher JC, Cohen-Solal A, Juillière Y. Plasma brain natriuretic peptide-guided therapy to improve outcome in heart failure: The STARS-BNP Multicenter Study. J Am Coll Cardiol. 2007; 49: 1733–1739.[Abstract/Free Full Text]

142. Shah MR, Claise KA, Bowers MT, Bhapkar M, Little J, Nohria A, Gaulden LH, McKee VK, Cozart KL, Mancinelli KL, Daniels H, Kinard T, Stevenson LW, Mancini DM, O’Connor CM, Califf RM. Testing new targets of therapy in advanced heart failure: the design and rationale of the Strategies for Tailoring Advanced Heart Failure Regimens in the Outpatient Setting: BRain NatrIuretic Peptide Versus the Clinical CongesTion ScorE (STARBRITE) trial. Am Heart J. 2005; 150: 893–898.[CrossRef][Medline] [Order article via Infotrieve]

143. Beck-da-Silva L, de Bold A, Fraser M, Williams K, Haddad H. BNP-guided therapy not better than expert’s clinical assessment for beta-blocker titration in patients with heart failure. Congest Heart Fail. 2005; 11: 248–253.[CrossRef][Medline] [Order article via Infotrieve]

144. O’Brien RJ, Squire IB, Demme B, Davies JE, Ng LL. Pre-discharge, but not admission, levels of NT-proBNP predict adverse prognosis following acute LVF. Eur J Heart Fail. 2003; 5: 499–506.[CrossRef][Medline] [Order article via Infotrieve]

145. Melzi d’Eril G, Tagnochetti T, Nauti A, Klersy C, Papalia A, Vadacca G, Moratti R, Merlini G. Biological variation of N-terminal pro-brain natriuretic peptide in healthy individuals. Clin Chem. 2003; 49: 1554–1555.[Free Full Text]

146. McGeoch G, Lainchbury J, Town GI, Toop L, Espiner E, Richards AM. Plasma brain natriuretic peptide after long-term treatment for heart failure in general practice. Eur J Heart Fail. 2002; 4: 479–483.[CrossRef][Medline] [Order article via Infotrieve]

147. Lainchbury JG, Troughton RW, Frampton CM, Yandle TG, Hamid A, Nicholls MG, Richards AM. NTproBNP-guided drug treatment for chronic heart failure: design and methods in the "BATTLESCARRED" trial. Eur J Heart Fail. 2006; 8: 532–538.[CrossRef][Medline] [Order article via Infotrieve]

148. Brunner-La Rocca HP, Buser PT, Schindler R, Bernheim A, Rickenbacher P, Pfisterer M. Management of elderly patients with congestive heart failure: design of the Trial of Intensified versus standard Medical therapy in Elderly patients with Congestive Heart Failure (TIME-CHF). Am Heart J. 2006; 151: 949–955.[CrossRef][Medline] [Order article via Infotrieve]

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