EXPERIMENTAL & CLINICAL CARDIOLOGY

Volume 20, Issue 1, 2014

Title: "Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease"

Authors: Raluca Haliga, Maria Apavaloaie and Magda Badescu

How to reference: Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive
Pulmonary Disease/Raluca Haliga, Maria Apavaloaie and Magda Badescu/Exp Clin Cardiol Vol 20
Issue1 pages 1606-1614 / 2014
 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

Natriuretic Peptides in Heart Failure Coexisting

with Chronic Obstructive Pulmonary Disease
Review Article

Haliga Raluca MD, PhD1,2, Apavaloaie Maria MD1,3, Badescu Magda MD, PhD1
1 Pathophysiology Department, University of Medicine and Pharmacy Gr.T.Popa, Iasi, Romania
2 Internal Medicine Clinic, St. Spiridon Hospital, Iasi, Romania
3 Cardiology Department, University of Medicine and Pharmacy Gr.T.Popa, Iasi, Romania

Correspondence: Apavaloaie Maria, Resident physician in Cardiology Department, University of Medicine and Pharmacy Gr.T.Popa,
Iasi, Romania. Telephone 004-0756-660770, e-mail maria_apavaloaie@yahoo.com

Abstract: Chronic obstructive pulmonary disease
(COPD) and heart failure (HF) frequently coexist in
clinical practice. Natriuretic peptides (NPs) - brain NP
(BNP) and∕or N-terminal proBNP (NT-proBNP) are
generally accepted to be useful for the diagnostic of HF,
even though there are other conditions which affect
serum levels of NPs, such as renal failure or COPD.
Cardiovascular disease (CVD) is an important cause of
mortality in COPD. Systemic inflammation is increased
in the course of COPD evolution, but significant during
exacerbations of COPD (ECOPD), providing a potential
mechanism to explain the increased risk of vascular
events associated with ECOPD. Recent findings
revealed that 95%–100% of patients are correctly
diagnosed in COPD coexisting with HF when NPs are
added to clinical judgment, considering the fact that
other methods of diagnostic have decreased sensitivity.
NPs levels can be increased in acute hypoxemic COPD,
although not as high as in manifest HF, possibly due to
pressure and/or volume load on the right ventricle. The
aim of this article is to ilustrate the most recent findings
revealing the pathophysiological relationships regarding
dyspnea in HF and COPD and how to manage the
diagnosis using the NPs.
Keywords: heart failure, chronic obstructive
pulmonary disease, dyspnea, natriuretic peptide,
inflammation.

INTRODUCTION – NATRIURETIC PEPTIDES AS nervous system, augmenting urine volume and sodium

CARDIAC HORMONES excretion and having a direct vasodilating effect [3].

The discovery of the cardiac endocrine function Brain natriuretic peptide (BNP) was first

more than 25 years ago was a breakthrough for the described in 1988, after being isolated from porcine

implementation of routine laboratory markers of heart brain [4], and was identified as a cardiac hormone. BNP

failure []. The natriuretic peptides (NPs) are is synthesized as a prehormone (proBNP), composed of

neurohormones [2]. There are 3 major NPs, atrial 108 aminoanids, which is further released into

natriuretic peptide (ANP), B-type natriuretic peptide circulation and cleaved into equal amounts of

(BNP), and C-type natriuretic peptide, all of which biologically active 32-amino-acid BNP, which

sharing a common 17-amino-acid ring structure [3]. represents the C-terminal fragment, and the

The NPs play important roles in the regulation biologically inactive 76-aminoacid N-terminal fragment

of water and sodium balance and in the homeostasis of (NT-proBNP) (figure 1). The main stimulus responsible

cardiovascular system [2]. They are released by for increasing BNP and NT-proBNP synthesis and

cardiomyocytes, as a response to stretching and their secretion is myocardial wall stress. Furthermore, factors

main actions consist of reducing the secretion of rennin such as myocardial ischemia and endocrine (paracrine)

and aldosterone, inhibiting the activity of adrenergic modulation by other neurohormones and cytokines are

also involved. The half-life of BNP is 20 min, whereas

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 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

NT-proBNP has a half-life of 120 min, this explaining reviewed recently identified biomarkers associated

why NT-proBNP serum values are approximately six with HF pathophysiology and concluded that the

times higher than BNP values, even though both biomarkers currently showing most promise, in terms

molecules are released in equimolar proportions [5]. of risk stratification, were Lp-PLA2 (marker of

inflammation), neutrophil gelatinase-associated lipocalin

and cystatin C (both representing renal stress),

procollagen-1-polypeptide (marker of extracellular

matrix remodelling), BNP, NT-proBNP, MR-proADM,

soluble ST2 receptor and copeptin (all representing

cardiac myocyte stress), and endothelin 1 (as

neurohormone regulation) [10 - 13].

BNP and NT-proBNP are generally accepted to

be useful for the diagnostic evaluation of patients with

Figure 1. Synthesis of BNP and NT-proBNP by cleavage of acute dyspnea [14]. However, there are many factors or
proBNP [6]
conditions, especially in elderly HF population, which
The release of BNP results in improved
can affect serum levels of NT-proBNP or BNP, such as
myocardial relaxation and has an important regulatory
renal failure, chronic obstructive pulmonary disease,
role in response to acute increases in ventricular
atrial fibrillation, stroke, infection (table 1), etc., not to
volume by opposing the vasoconstriction, sodium
mention of higher age [15].
retention, and antidiuretic effects of the activated renin-
Diseases with increase in BNP and NT-proBNP
angiotensin-aldosterone system [6, 7]. The biological
 Acute or chronic systolic or diastolic HF
actions of NPs are mediated through membrane-bound  LV hypertrophy
NPs receptors (NPRs), that are linked to a cyclic  Inflammatory cardiac diseases
 Systemic arterial hypertension with LVH
guanosine monophosphate-dependent signaling cascade,
 Pulmonary arterial hypertension
including NPR-A, which preferentially binds ANP and  Acute or chronic renal failure
BNP, and NPR-B, which preferentially binds C-type  Liver cirrhosis with ascites
 Endocrine disorders (hyperthyroidism, Cushing
NP. Clearance of NPs from the blood is mediated by
syndrome, hyperaldosteronism)
NPR-C [3].
 Anemia
NATRIURETIC PEPTIDES IN HEART FAILURE  CNS diseases (stroke, subarachnoid hemorrhage)
Heart failure (HF) is a complex syndrome with  Paraneoplastic syndrome
Table 1. Cardiac and extracardiac conditions associated with
high morbidity and mortality, in whose development
increased NPs levels [16]
and progression are implicated myocardial injury,
A recent metaanalysis analyzing data from 40
hemodynamic overload, genetic, neurohormonal,
long-term prospective studies involving a total of
inflammatory and biochemical factors. Despite the
87.474 participants and 10.625 incident cardiovascular
development of several diagnostic tests, HF diagnosis
outcomes confirmed that a proportional rise in BNP or
remains clinical based on symptoms and signs, while
NT-proBNP levels is similarly associated with
there is a poor relationship between symptoms and
increased cardiovascular risk [17]. Recent studies also
prognosis of HF [8].
investigated the levels of BNP and∕or NT-proBNP in
Many pathophysiological mechanisms contribute
patients with acute or chronic dyspnea in cardiac
to the development of HF. Avellino and colleagues [9]

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 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

disorders progressing to HF. Thus, in the Breathing Not Another study demonstrated that elevated BNP levels

Properly (BNP) Multinational Study, BNP levels reinforced the diagnostic of diastolic dysfunction even

measured on arrival in 1,586 emergency department in patients with normal systolic function [22]. In the

(ED) patients presenting with acute dyspnea had higher same sense, a study which investigated the plasma

diagnostic accuracy than did the clinical exam in level of BNP in patients with diastolic HF (DHF) and

diagnosing HF [3]. Also, the same trial reported that left ventricular hypertrophy (LVH) concluded that an

NPs levels were elevated in patients with a history of elevation of BNP may be a hallmark of patients with or

HF who present with dyspnea, but without an acute HF at high risk of DHF among subjects with preserved

exacerbation. The results of this trial showed that the systolic function independent of LVH [23]. Even in the

BNP levels of the patients tend to be intermediate, absence of concomitant HF, studies showed that acute

between those without HF and those with an acute HF coronary syndrome (ACS) is associated with a rise in

diagnosis [ ]. In the PRIDE (ProBNP Investigation of

18 NP levels. The degree of elevation might reflect the

Dyspnea in the Emergency Department) study severity of LV dysfunction [24]. Some authors suggested

performed in 600 patients who presented to a single ED the use of NPs levels as a guide to institute more

with dyspnea, NTproBNP was sensitive and specific for aggressive treatments in ACS, aiming to reduce the

the diagnosis of congestive HF (CHF) [3,19]. Other ventricular wall stress [25].

studies reported that BNP and NT-proBNP correlate COEXISTENCE OF HEART FAILURE WITH

with New York Heart Association class of HF [20]. CHRONIC OBSTRUCTIVE PULMONARY DISEASE

Recent studies investigated the relationship – ROLE OF NATRIURETIC PEPTIDES

between cardiac marker BNP and echocardiographic Chronic obstructive pulmonary disease (COPD)

exam in order to find a better way to assess systolic and heart failure (HF) frequently coexist in clinical

and∕or diastolic dysfunction in HF diagnostic. The practice [26]. Both conditions share some common risk

levels of BNP demonstrated also to be useful in factors, including cigarette smoking, advanced age, and

establishing the diagnosis of diastolic dysfunction in systemic inflammation [27, 28]. According to the Global

acute HF patients. Studies revealed that as diastolic Initiative for Chronic Obstructive Lung Disease (GOLD),

dysfunction increases in severity, assessed by Doppler patients with COPD are at higher risk for

filling patterns of mitral inflow and pulmonary venous cardiovascular diseases, which is a result of general

flow, BNP levels rise accordingly, representing a inflammatory process [2].

reflection of LV end-diastolic wall stress [3]. Thus, a The prevalence of COPD among individuals

study of Iwanaga et al [ ] reported that plasma BNP

21 with HF ranges from 20% to 32% of cases, and 10% of

levels reflected left ventricular end-dyastolic wall stress hospitalized HF patients also suffer COPD [28]. From

(EDWS) more than any other parameter previously the opposite side, HF is prevalent in more than 20% of

described, and not only in patients with systolic heart patients with COPD [29,30]. Moreover, the risk ratio of

failure (SHF), but also in those with diastolic heart developing HF among COPD patients is 4.5 times

failure (DHF). The authors also concluded that the higher than that of control individuals without the

relationship of left ventricular EDWS to plasma BNP disease, after adjusting for age and other cardiovascular

may provide a better fundamental understanding in the risk factors [31]. Several large trials found that the most

interindividual heterogeneity of BNP levels and their frequent cause of death among patients with COPD is

clinical utility in the diagnostic and management of HF. cardiac, rather than respiratory complications [5].

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 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

Recognising HF in the presence of COPD and systemic inflammation appears to be an important one

vice versa is complicated by similarities in symptoms [39,40]. Systemic inflammation is increased in course of

and physical finding. Furthermore, chest radiography COPD evolution, but significant during ECOPD [41]

or electrocardiographic abnormalities have a decreased providing a potential mechanism to explain the

sensitivity, but also echocardiography and pulmonary increased risk of vascular events associated with

function testing. Echocardiographic windows can be ECOPD. Fabbri et al reported about three studies

limited by hyperinflated lungs and can complicate providing new informations that contribute to a better

precise measurements in up to 10–30% of COPD understanding of the relationship between ECOPD,

patients [32]. Cardiovascular magnetic resonance inflammation and cardiovascular events [37]. From these

imaging (CMR) could serve as an alternative for studies, the first two studies [42,43] found the plasma

echocardiography in these patients, since CMR is not levels of the cardiac biomarkers NT-proBNP and

affected by hyperinflated lungs, but is more expensive troponin T increased in a significant number of patients

than echocardiography. NPs, such as BNP and NT- hospitalised because of ECOPD, and both markers

proBNP, can help the clinician in differentiating COPD predicted mortality even after adjusting for other

from HF in patients with acute dyspnoea [33]. NPs predictors of mortality, such as PaCO2 or CURB65 score

levels can be increased in acute hypoxemic COPD, (composite index based on confusion, blood urea,

although not as high as in manifest HF, possibly due to respiratory rate, blood pressure and age developed to

pressure and/or volume load on the right ventricle [34]. predict mortality risk in community-acquired

Cardiovascular disease (CVD) is an important pneumonia). The third study found that, compared

cause of mortality in COPD [35] and, as recently shown with healthy controls, patients with COPD had

by Donaldson et al [ ] the risk of acute vascular events

36 increased circulating platelet-monocyte aggregates,

appears to be particularly higher during episodes of which were further increased during ECOPD [37,44].

exacerbations of COPD (ECOPD). Data from 25.857 Inflammation is an important process in HF and

patients with COPD who entered in the Health that is why mediators of inflammation have been

Improvement Network database over a 2-year period studied as potential biomarkers in HF [13]. The first

reported that the risk of myocardial infarction 1-5 days report of inflammatory markers in HF sustained that C-

after an ECOPD episode increased 2.3-fold and the risk reactive protein (CRP) concentrations were increased in

of stroke 1-49 days after ECOPD increased 1.3-fold chronic HF patients and that absolute concentrations

[36,37]. As a matter of fact, infection is one of the most were indicative for severity of disease [45]. CRP

common causes that aggravate HF leading to mediates several protective processes, but may also

hospitalization. ECOPD are usually diagnosed when have deleterious effects in HF, such as upregulation of

other causes of decompensation have been eliminated. tumor necrosis factor alpha (TNF-alpha) and IL-6.

Left ventricular dysfunction (LVD) is often present in Although recent studies confirmed a prognostic role for

patients with ECOPD, but can remain insidious, being a CRP in HF, it might be less suitable as a biomarker for

known or unknown comorbidity due to the frequent HF because of its promiscuous role in various

association of two diseases sharing the same risk factors inflammatory processes and the lack of a therapeutic

(smoking and inflammation) [38] . imperative associated with its increase [46,47].

The mechanisms linking COPD and CVD are A theory to explain the high prevalence of left

still unclear, but the presence of low-grade chronic ventricular systolic dysfunction in COPD patients is

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 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

that systemic inflammation would accelerate coronary Also, even if not specifically tested in patients with a

atherosclerosis progression, leading to development of history of COPD, BNP > 500 pg/mL is suggested by

ischemic heart disease. The high incidence of motor several authors to indicate acute HF in COPD patients

alterations in the left ventricular wall and LVD that are [48,49]. For NT-proBNP, a value < 300 pg/mL excludes

observed in COPD patients could also explain the HF, and a value > 450 pg/mL (for patients < 50 years) or

relationship between these chronic progressive diseases a value > 900 pg/mL (for those ≥50 years) identifies HF

[28]. Studies reported that in patients with COPD, in patients with previous COPD presenting with acute

plasma levels of NPs are a fast and sensitive biomarker dyspnea (table 2). For excluding HF, the sensitivity was

for diagnosing HF. Thus, the BNP cutoff point for 94%, while for detecting HF, the specificity was 84%. It

excluding or detecting HF is 100 pg/mL. BNP levels should be noted that 95%–100% of patients are correctly

ranging from 100 pg/mL to 500 pg/mL in COPD diagnosed when NPs are added to clinical judgment

patients may be due to cor pulmonale (right ventricular [50,51].

stretch), moderate left ventricular failure, or both [28].

BNP < 100 pg∕mL 100-500 pg∕mL >500 pg∕mL

NT-proBNP < 300 pg∕mL Gray zone  < 50 y > 450 pg∕mL

 50-75 y > 900 pg∕mL

 > 75 y > 1800 pg∕mL

Interpretation HF unlikely Gray zone HF likely

Diagnosis by imaging Confirmation by imaging

(Echocardiography) (Echocardiography)
Table 2. Interpretation of BNP and NT-proBNP levels in patients with acute dyspnea without severe renal failure [16]

In a recent study, NPs remained accurate life-threatening etiologies, including pulmonary

indicators of LVD associated with ECOPD in the setting embolism, must still be excluded, especially when NP

of renal failure, because hypoxaemia, pulmonary levels fall within the "gray zone" (BNP 100 to 500 pg/ml;

hypertension and right heart dysfunction combined NTproBNP 300 to 900 pg/ml for 50- to 75-year-olds) [55].

with impaired NPs renal removal to increase the Recent studies regarding the diagnostic utility of

threshold levels of circulating NPs [38]. Right heart NT-proBNP for determining COPD severity reported

dysfunction due to severe lung disease from a variety that NT-proBNP levels increased significantly with

of etiologies can cause elevated NP levels [3]. The disease severity, being the highest in patients with

mechanism is likely due to release of peptide from the stage III and IV of COPD; also, plasma NT-proBNP

right ventricular myocardium [52], although decreased concentrations significantly correlated with chronic

lung expression of the NPR-C clearance receptor in respiratory failure and was associated with systolic

response to hypoxia has been demonstrated in animal pulmonary artery pressure [5,42]. These results can be

models [53]. This situation can be found in severe explained by the fact that, during COPD progression,

COPD, primary pulmonary hypertension, and other decreased FEV1 may lead to increased air-trapping and

causes of pulmonary hypertension [52,54]. Because of hyperinflation of the lungs; hyperinflation can be

this, when evaluating acutely dyspneic patients, it is associated with decreased cardiac function and may

important to note that elevated NP levels are not result in an increase of plasma NT-proBNP. Another

pathognomonic for CHF, and also another potentially explanation might be related to hypoxia or hypercapnia

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 Natriuretic Peptides in Heart Failure Coexisting with Chronic Obstructive Pulmonary Disease

in patients with COPD. Chronic hypoxia induced by HF, in comparison to COPD patients without

progression of COPD could result in contraction of the comorbidities [2].

small pulmonary arterioles, resulting in increased In conclusion, plasma BNP and NT-proBNP are

pulmonary arterial systolic pressure and increased parameters often used in HF care in clinical practice.

plasma NT-proBNP levels, by rising right ventricular Many recent studies demonstrated that inflammation is

pressure overload [5]. able to induce higher increasing of NPs levels in

On the other hand, Rubinsztajn et al. assessed patients with chronic HF, indicating that BNP and NT-

the usefulness of NT-proBNP blood levels in patients proBNP should be evaluated concomitantly with

with stable COPD complaining of chronic dyspnea and inflammatory status to avoid overestimation of HF

reported that there were no significant differences in severity. Furthermore, both NT-proBNP and BNP are

serum NT-proBNP levels depending on the disease useful prognostic biomarkers, but they need to be

severity or on the BODE (body mass index, airflow interpreted with caution when concomitant diseases

obstruction, dyspnoea, exercise capacity) index in the exist, such as COPD or renal failure, and patients are

stable stages of COPD, but NT-proBNP levels were very old, because patients may die also due to non-

significantly higher in patients in whom COPD cardiac causes.

coexisted with circulatory system diseases, especially

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