The Diagnostic Value of B Natriuretic Peptide in Elderly Patients with Acute Dyspnea

Abstract

Introduction

The number of emergency department (ED) admissions continues to climb, with a limited number of departments available to handle the volume.¹ The rapid and accurate diagnosis of dyspneic patients is a routine challenge for ED physicians. Unfortunately, the signs and symptoms of congestive heart failure (CHF) - the first cause of dyspnea—are frequently non specific and highly variable especially in older adults or patients with pre-existing respiratory diseases.^2–4 Indeed, CHF can present as wheezing and mimic acute asthma (so-called cardiac asthma) especially in the elderly.⁵ Recent studies suggested that an appropriate diagnosis and early accurate therapy were associated with a decreased mortality and morbidity from acute dyspnea and CHF.^6,7 Natriuretic peptides (NP) (including atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type natriuretic peptide (CNP)) are endogenous hormones that are released by the heart in response to myocardial stretch and overload. In this article, the rationale and value of BNP for emergency patients admitted for acute dyspnea are reviewed.^6,7,8

Role of the Natriuretic Peptides in Heart Failure

Physiologic secretion of natriuretic peptides

Cardiac endocrine function is an essential component of the homeostatic regulation network,^9,10 including the renin-angiotensin-aldosterone system, vasopressin, endothelins, and sympathetic nervous system, and the counter-regulatory vasodilatory/natriuretic response, mainly represented by NP.¹¹ As cardiac performance decreases, all neurohormonal systems are progressively stimulated in an attempt to sustain cardiac output and circulatory homeostasis.¹² The large increases in circulating concentrations of NP in HF could be related to activation of the neuroendocrine system and thus be considered an adaptive and potentially protective response mechanism in cardiovascular disease.

NP have several physiologic actions, the most important being (a) vasodilation; (b) promotion of natriuresis and diuresis; (c) inhibition of the sympathetic nervous system and of the renin-angiotensin-aldosterone system, endothelins, cytokines, and vasopressin; (d) inhibition of the pathophysiologic mechanisms responsible for ventricular and vascular hypertrophy and remodeling; and (e) beneficial effects on endothelial dysfunction secondary to the atherosclerotic process, including blunting of shear stress and regulation of coagulation and fibrinolysis, as well as inhibition of platelet activation.^12,13

The NP family includes ANP, BNP and its related peptide, whereas CNP and urodilatin are predominantly secreted by noncardiac tissues (endothelium and kidney, respectively). Recently, another peptide, called dendroaspis natriuretic peptide (DNP), with a structure and biological activities similar to those of the NP family, was identified, but its role is still uncertain.^14,15

BNP derives from the precursor pre-proBNP, containing 134 amino acids and including a signal peptide of 26 amino acids. ProBNP, produced by cleavage of the signal peptide, is further split into BNP, which is considered to be the biologically active hormone, and an inactive N-amino terminal fragment, NT-proBNP. NT-proBNP is used in a commercial analytical method and refers to measurement of N-terminal 1-76 fragment. BNP is a 32-aa polypeptide containing a 17-aa ring structure common to all NPs.⁶ BNP gene expression is a feature of both atrial and ventricular myocytes. In the healthy heart, BNP gene expression occurs mainly in the atria. However, ventricular BNP gene expression is up-regulated in diseases that affect the ventricles, such as CHF. Atrial myocytes contain secretory granules for peptide storage.¹² Importantly, atrial granules store both intact proBNP and cleaved products, i.e. bioactive BNP-32. In contrast, ventricular myocytes in the healthy heart do not seem to produce these granules, and do not contain proBNP-derived peptides. The nucleic acid sequence of the BNP gene contains the destabilizing sequence TATTTAT, which suggests that turnover of BNP messenger RNA is high and that BNP is synthesized in bursts. This release appears to be directly proportional to ventricular volume expansion and pressure overload.

The elimination of the two peptides is different.¹⁶ BNP is cleared by several mechanisms, including the kidneys, specific clearance receptor-mediated degradation (natruretic peptide receptor type C, NPR-C) and enzymatic degradation, especially neutral endopeptidase. In contrast, NT-proBNP seems to be removed exclusively by the kidneys.¹⁷ These differences are responsible for the fact that BNP has a lower absolute plasma concentration. However, Kroll et al. recently recalculated the NT-proBNP half-life and found that it was closer to that of BNP (25 minutes).¹⁸ ANP has a half-life of 1 to 5 minutes.¹⁹

Factors related to natriuretic peptide secretions

NP are greatly increased in diseases characterized by an expanded fluid volume. The common clinical conditions affecting the circulating concentrations of NPs are shown in Table 1.²⁰ The circulating concentrations of NP are also directly or indirectly modified by several physiologic factors, such as circadian variations, sodium intake and drugs or hormones (including corticosteroids, diuretics, angiotensin-converting enzyme inhibitors, adrenergic agonists and adrenergic antagonists) or pro-inflammatory cytokines.^19,46

Table 1.

Causes of raised BNP and NT-proBNP levels.

Congestive heart failure (CHF) Septic shock

Right or Left ventricular dysfunction, without acute

CHF

Coronary artery disease, atrial fibrillation

Acute respiratory distress syndrome

Acute pulmonary embolism

Chronic obstructive pulmonary disease with cor pulmonale

Renal failure

Liver cirrhosis

Subarachnoid hemorrhage

Hyperthyroidism

However, the main variations in circulating concentrations of NP in healthy adults are related to weight, aging and gender. In particular, the BNP concentration is about one third higher in women than in men.²¹ It could be explained by the physiologic stimulation of female sex steroid hormones. The increases in NP with aging may be attributable to physiologic cardiac hypertrophy and kidney's senescence (decrease in their clearance rate).²² When adjusted for relevant covariates, compared with normal counterparts, overweight and obese patients with acute CHF have lower circulating NT-proBNP and BNP levels, suggesting a body mass index-related defect in natriuretic peptide secretion.²³ A recent study suggested that the association between BMI and BNP and NT-proBNP could be mediated by lean mass rather than fat mass.²³ In fact, studies on effect of obesity on NP are controversial.²⁴

BNP and NT-proBNP: diagnostic role in dyspnea

BNP is an independent predictor of high left ventricular end-diastolic pressure and of capillary pulmonary artery pressure.²⁵ Both correlate to New York Heart Association classification, to the severity of heart failure, and correlate inversely to left ventricular ejection fraction.²⁶ Cardiologic studies showed that BNP and NT-proBNP can reliably predict the presence or absence of left ventricular dysfunction on echocardiography.

The potential clinical usefulness of assays of NP for differential diagnosis of dyspnea and for stratification of patients with CHF has been confirmed over the last five years. Thus, the Task Force of the European Society of Cardiology recommended that a BNP assay should be included in the first step of the algorithm for the diagnosis of HF as are electrocardiography (ECG) and chest x-rays.²⁷

Acute dyspnea is the key symptom of most respiratory diseases and CHF, with high related morbidity and mortality.²⁸ Unfortunately, the accuracy in diagnosing CHF by emergency physicians is about 60%.^28,29 In the EPIDASA study,²⁸ 514 patients older than 65 years with acute dyspnea were included. The in-hospital mortality was 16%, with a higher mortality (21%) in the 219 patients with CHF. Inappropriate emergency treatment occurred in 162 (32%) patients, and led to a higher mortality (25% versus 11%; p < 0.001), highlighting the importance of an early accurate treatment in the ED.

Numerous studies have evaluated and validated both natriuretic peptides in the diagnosis of CHF in middle-aged patients with acute dyspneoa^26,30–41 (Tables 2 and 3). All studies used the same methodology, with a measurement of BNP at admission in dyspneic patients in the emergency room. The final diagnosis of CHF related-dyspnea was adjudicated by independent experts, who were blinded to the results of the BNP assay, and the complete medical chart. The usual exclusion criteria were patients with severe renal insufficiency patients whose dyspnea was clearly not secondary to CHF (chest trauma), and dyspnea secondary to severe coronary ischemia. The largest studies was performed by Maisel et al.⁶ In the BNP (breathless not properly) study, value of 100 pg/ml or more for BNP was the strongest independent predictor of CHF, with an odds ratio of 29.60. A BNP cutoff of 100 pg/ml was more accurate (83%) than either the NHANES criteria (67%) or the Framingham criteria (73%), two commonly used sets of criteria for diagnosing CHF. The diagnostic accuracy of BNP was 83.4% with an area under the receiver-operating-characteristic curve (AUC) of 0.91.⁶ The PRIDE (ProBNP Investigation of Dyspnea in the Emergency Department) study included 600 patients.⁴² The ROC curve demonstrated NT-proBNP to be highly sensitive and specific for the diagnosis of acute CHF (AUC of 0.94), with an optimal cutpoint of 900 pg/mL. Increased NT-proBNP was the strongest independent predictor of a final diagnosis of acute CHF (odds ratio 44). NT-proBNP testing alone was superior to clinical judgment alone for diagnosing acute CHF. Using an age categorization of <50 years (n = 144) and ≥50 years (n = 455), Januzzi et al. determined that—for ruling in acute CHF—the optimal cut off points were 450 and 900 pg/ml with areas under the curve of 0.98 and 0.93, respectively. Recently, Moe⁴⁴ et al. confirmed that clinical judgment alone generated a lower AUC than NT-proBNP (0.83 vs. 0.90) (see below).

Table 2.

Summary of studies which evaluated diagnostic accuracy of BNP (TriageBNP^®).

BNP	Logeart (37)	Dao (35)	Lainchbury (36)	Maisel (6)	Ray (40)
Number of patients	166	321	205	1586	308
Mean age	67	ND	70	64	80
% acute CHF	70	42	34	47	46
Threshold value (pg/mL)	300	94	208	100	250
Sensitivity (%)	88	86	94	90	78
Specificity (%)	87	98	70	76	90

Table 3.

Summary of studies which evaluated diagnostic accuracy of NT-proBNP (Elecsys^®).

NT-proBNP	Bayes-Génis (31)	Januzzi (42)	Ray (39)	Berdague (32)	Moe (52)	Zaninotto (41)
Number of patients	100	599	202	256	500	122
Mean age	70	70	80	81	70	78
% acute CHF	58	37	44	55	46	46
Threshold value (pg/mL)	1000	900	1500	2000	NA	1800
Sensitivity (%)	91	87	75	86	NA (about 78)	80
Spécificity (%)	90	86	76	71	NA (about 80)	76

Grossly, the higher is the mean age of the population evaluated, the higher is the threshold value of BNP and NT-proBNP

Specific considerations in the elderly

To our knowledge, few studies have specifically evaluated BNP and NT-proBNP in elderly patients^{32,39,40,43,44} (Table 3). Ray et al. demonstrated that increased BNP was the strongest independent predictor of a final diagnosis of CHF (odds ratio 24.4, p < 0.001), and the accuracy of BNP-assisted diagnosis was higher than that of the emergency physician (0.84 versus 0.77, p < 0.05). They also showed that, whatever the empirical probability (from absent to very likely) estimated by the emergency physician for CHF, an elevated level of BNP higher than 250 pg/ml was an accurate predictor of CHF (positive likelihood ratio from 5.9 to 8.8 respectively). Berdague et al. assessed the usefulness of NT-proBNP assay for the diagnosis of CHF in 256 elderly patients (mean age 81 years). The diagnoses made in the ED were incorrect or uncertain in 45% of cases. The median NT-proBNP value was higher (p < 0.0001) in patients with cardiac dyspnea (56%; 7906 pg/ml) than in patients with non—cardiac dyspnea (44%; 1066 pg/ml). NT-proBNP >2000 pg/ml was the most powerful independent marker of cardiac dyspnea (odds ratio 13.6, p < 0.001). In 241 elderly patients, Arques et al. demonstrated that BNP was as accurate as bedside tissue Doppler echocardiography (0.928 for BNP with a threshold value of 253 pg/ml vs. AUC of 0.846 for echocardiography) for predicting CHF with preserved left ventricular systolic function.⁴⁵ In 155 patients presenting with acute dyspnea, Knudsen et al. demonstrated that BNP cut-off was close to 200 pg/mL and that AUC were 0.82 and 0.88 for patients (both genders) aged ≥76 and <76 years, respectively.⁴⁴

BNP in clinical practice

Overall, BNP and NT-proBNP threshold values were more elevated in patients aged ≥65 years, compared with younger patients. CHF appears to be highly unlikely below a BNP plasma concentration of 100 pg/ml, or a NT-proBNP below 500 pg/mL, and CHF appears to be likely when plasma concentration of BNP is higher than 500 pg/ml, or NT-proBNP is greater 2000 pg/mL (Fig. 1). The choice of these two cut-off 100 and 500 pg/mL is based on the fact that i) the lower cut-off (100 pg/mL) corresponds to the diagnostic threshold level for CHF recommended by the manufacturer and by Maisel's study; ii) the upper cut-off corresponds to a marked increase in the probability of the diagnosis of CHF.^40,46,47 In the BNP study, of 472 patients with BNP values greater than 500 pg/mL, 87% had CHF. Furthermore, in the BASEL study (see below), Mueller et al. used this two cut-off.⁷

Figure 1.

Diagnostic strategy based on B-type natriuretic peptide levels in elderly patients admitted for ARF in the emergency department.

Between these situations (so-called “the grey zone”), further investigations are needed (such as Doppler-echocardiography, spiral chest CT.) since many causes might be suspected including atrial fibrillation without CHF, pulmonary embolism (PE) and exacerbation of COPD (chronic obstructive respiratory disease) and CHF.^40,46,47 Thus, in the BNP study, 61% of patients with BNP values between 100 and 500 pg/mL had a final diagnosis of CHF. Other predictors of elevated BNP levels include a decreased blood hemoglobin concentration, decreased body mass index, increased age.^40,47

All these findings strongly support the position adopted by recently published HF consensus guidelines that advocate the use of BNP or NT-proBNP as a complement to clinical assessment.^27,48

Comparison of BNP and NT-proBNP

There is a strong relationship between heart failure (and thus BNP and NT-proBNP concentrations) and renal function. The central questions are i) how to interpret BNP and NT-proBNP concentrations in patients with renal impairment? ii) is BNP superior to NT-proBNP in case of renal dysfunction? Januzzi et al. found that NT-proBNP and eGFR (glomerular filtration rate) were inversely and independently related.⁴⁹ McCullough et al. showed that BNP concentrations and cut-off points were influenced by renal function, when eGFR was less than 60 mL/min/1.73 m2.⁵⁰ Chenevier-Gobeaux et al. showed that i) both NT-proBNP and BNP values were inversely correlated to eGFR, and ii) NT-proBNP and BNP cut-off points rose in line with CKD levels.³⁴ Ray et al. included 202 patients (mean age of 80 years); 88 (44%) had CHF. The ROC curve showed that BNP and NT-proBNP accurately diagnosed CHF, but the AUC for NT-proBNP was lower than that of BNP (0.80 vs. 0.85, p < 0.05).³⁹ Using logistic regression, only the diagnosis of CHF predicted the elevation of BNP greater than 250 pg/mL (OR = 27.7, p < 0.001). Conversely, the diagnosis of CHF (odds ratio 11.7) and a creatinine clearance of less than 60 mL/min (odds ratio 2.7) independently predicted the elevation of NT-proBNP greater than 1,500 pg/mL. Renal dysfunction might at least partly explain the lower accuracy of NT-proBNP observed, because in contrast to BNP, renal excretion is a major route of elimination of NT-proBNP.³⁹

However, other studies which compared the diagnostic accuracy of BNP and NT-proBNP did not confirm this finding.^32,51 In a subgroup (n = 75) analysis of their study, Berdague et al. demonstrated that AUC was 0.86 for BNP measurement compared with 0.88 for NT-proBNP (p = 0.6). In 160 patients over 75 years of age, Alibay et al. demonstrated that the diagnostic value, assessed by the AUC, was similar for BNP (0.82) and NT-proBNP (0.84).⁵¹ Mueller et al. demonstrated that AUC for BNP and NT-proBNP in patients with dyspnoea did not differ significantly (AUC of 0.916 vs. 0.903).³⁸ In 381 patients (mean age 79 years) with dyspnoea,³⁴ Chenevier-Gobeaux et al. found that NT-proBNP and BNP concentrations increased in a similar way when eGFR decreased.

Overall, BNP and NT-proBNP might be equally useful as an aid in the diagnosis of CHF in elderly patients presenting to the ED with shortness of breath (Tables 4 and 5). Thus, biologists and physicians should base their decision as to the assay to be performed on reasons and considerations other than their diagnostic value (e.g. cost, bedside utilization, in vitro stability, practical availability, etc.).

Table 4.

Characteristics of BNP vs. NT-proBNP.

Characteristic	BNP	NT-proBNP
Components	BNP active hormone	NT fragment (1-76) bi-product
Molecular weight	4 kilodaltons	8.5 kilodaltons
Genesis	Cleavage from proBNP	Cleavage from proBNP
Half-life	20 minutes	90 minutes “classically”
Clearance mechanism	Neutral endopeptidase Clearance receptors Renal clearance	Renal clearance +++
Increases with aging	+++	++++
Correlation with eGFR	-0.20	-0.60
Approved cutoff(s) for CHF diagnosis	100 pg/mL Age ≥75: 250 pg/mL	Age <75: 900 pg/mL Age ≥75: 1550 pg/mL
Prognostic role in CHF	+++	+++
Prognostic role in severe PE	++	++

Table 5.

Comparison between BNP and NT-proBNP.

	Mueller (38)	Chenevier-Gobeaux (34)	Alibay (30)	Lainchbury (36)	Ray (39)
Number of patients	251	381	160	205	202
Mean age	73	79	81	70	80
AUC BNP	92	80	82	89	85
AUC NT-proBNP	90	73	84	89	80

Do measurement of B natriuretic peptides improve outcome?

There is now evidence that early measurement of BNP or NT-proBNP following admission to the ED could improve the outcome of dyspneic patients. Mueller et al. conducted a prospective, randomized, controlled study of 452 patients who presented in the ED with acute dyspnea. 225 patients were randomly assigned to a diagnostic strategy involving the measurement of BNP levels with the use of a rapid bedside assay, and 227 were assessed in a standard manner. The use of BNP levels reduced the need for hospitalization (75% vs. 85%), the length of stay (8 vs. 11 days), and their care cost ($5410 vs. $7264) than those whose physicians used conventional assessment. The respective 30-day mortality rates were unchanged. However, a significant reduction in 30-day mortality was observed (9% in the BNP group vs. 17% in the control group; p = 0.039) in the subgroup of patients older than 70 years.⁷ Of note (see Fig. 1), in the BNP group, BNP level was associated with strong recommendations for treatment and management, especially if CHF.

Moe et al. also demonstrated that NT-proBNP testing improves the management of 500 patients (Mean age 70) presenting with dyspnea in the ED by prospectively comparing the clinical and economic impact of a randomized management strategy either guided by NT-proBNP results or without knowledge of NT-proBNP concentrations.⁵² Knowledge of NT-proBNP results reduced the number of patients re—hospitalized over 60 days by 35% (51 to 33%), and direct medical costs of all ED visits, hospitalizations, and subsequent outpatient services (U.S. $6129 to U.S. $5180 per patient) over 60 days from enrollment. However, knowledge of NT-proBNP results did not result in any major improvement in rate of hospitalization, hospital length of stay, or mortality rates.

Overall, knowledge the level of BNP or NT-proBNP during initial evaluation in the ED is associated with lower costs.

There is also evidence that a BNP or NT-proBNP-guided strategy could improve morbidity related to CHF.53-55 For example, Jourdain et al. reported that a BNP-guided therapeutic strategy was superior to a clinically guided approach in 200 NYHA functional class II to III patients (mean age of 65 years) considered optimally treated by CHF specialists.^53–55 During a median follow-up of 15 months, fewer patients in the BNP group reached the combined end point of CHF-related death or hospital stay for CHF (24% vs. 52%). The main reason for the more favorable outcome of the BNP group was that mean dosages of ACEIs (angiotensin-converting enzyme inhibitors) and beta-blockers were significantly greater in the BNP group. Other studies are currently conducted to determine whether titration of drug treatment according to plasma NT-proBNP is superior regarding clinical outcomes to that provided by intensive standardized clinical assessment.⁵⁶

Prognostic values of B natriuretic peptides assessment in acute dyspnea prognostic value in acute dyspnea and CHF

In acute dyspnea, studies suggest that high BNP or NT-proBNP levels at admission could be of prognostic importance^57–61 Januzzi et al. demonstrated that NT-proBNP at the time of presentation was not only diagnostically useful, but also strongly predicted likelihood for short-term mortality in subjects with CHF, with a more than five-fold increase in risk for death by 76 days among those with marked elevation in NT-proBNP concentrations.⁶⁰ Gegenhuber et al.⁵⁸ followed up 251 consecutive patients (mean age of 72 years) admitted for shortness of breath in an ED. Within one year from the time they were enrolled, 62 died and 189 remained alive. Mortality was higher in patients with baseline BNP and NT-proBNP concentrations above the cut off levels (454 pg/mL and 2060 pg/mL, respectively). Lastly, in a multivariate analysis of the EPIDASA study, elevated NT-proBNP or BNP (odds ratio 2.06) was also predictive of death.²⁸ However, other studies suggest that BNP or NT-proBNP values at pre—discharge,⁶² and/or percentage change in BNP levels during hospitalization rather than at admission could be more accurate for predicting long-term outcome in patients admitted for acute CHF.⁶¹ Logeart et al. demonstrated that patients with BNP <350 pg/ml had the best outcome (16.2% of events at 6 months) compared with patients with BNP between 350 and 700 pg/ml (60%) and patients with BNP >700 pg/ml (93%). Recently, Chenevier-Gobeaux et al.⁸ reported NT-proBNP higher than 3,855 pg/ml—at admission—was associated with significant higher in-hospital mortality in 324 patients aged 75 years and over admitted for dyspnea (17.9% vs. 9.7%). Elevated NT-proBNP concentration at admission was the only variable predictive of death (odds ratio 2.41) Furthermore, mortality in patients with positive cTnI (n = 54) was higher when patients had NT-proBNP ≥3,855 pg/mL than in patients with NT-proBNP <3,855 pg/mL (32.5% vs. 7.1%, p = 0.082).⁸ Christ et al. also reported that elevated levels of BNP and cardiac troponin I levels were independently associated with an increased risk of death during long-term follow-up.⁶³

Prognostic value in PE

Some subgroups of patients with pulmonary embolism (PE) have a high risk, especially patients with hemodynamic impairment (massive PE), but also hemodynamically stable patients with right ventricular dysfunction (so-called sub—massive PE). Indeed, right ventricular dysfunction is the main determinant of the short-term course of PE and could provide guidance for the early management of patients with PE. Some authors have suggested that thrombolytic therapy could be indicated for submassive PE. BNP and NT-proBNP seem to be useful markers of right ventricular dysfunction and initial myocardial injury in acute PE. Like in acute coronary syndrome,⁶⁴ studies have suggested that BNP or NT-pro-BNP were accurate in risk stratification for PE had a high positive negative value for in-hospital death.^65–68 However, other studies have not shown any prognostic usefulness.⁶⁹ In elderly patients, BNP and NT-proBNP do not seem to be solid tests to identify patients with a risk of complicated PE.^70,71 Thus, in clinical practice the measurement of BNP or NT-proBNP level for each PE admitted to an ED cannot be recommended.

Conclusions

There is strong evidence that BNP and NT-proBNP are reliable markers of CHF in acute dyspnea. Furthermore, they add a prognostic value. Used in conjunction with other clinical information, rapid measurement of BNP or NT-proBNP has been shown to reduce total patient treatment cost. As recommended by current guidelines, their measurements should be strongly promoted in ED.

Footnotes

Acknowledgements

We thank Dr. D. Baker, M.D., Ph.D., FRCA (Department of Anesthesiology, CHU Necker-Enfants malades, Paris, France) for reviewing the manuscript.

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