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&#40;pathophysiological inability to synthesize and secrete natriuretic peptides&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a> Although these trials do not show decisively that modulation of natriuretic peptides is the way forward for the individualized treatment of HF patients&#44; it still has considerable potential and hence remains under investigation&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The medical world was recently startled by the results of a study &#40;PARADIGM-HF&#41; that compared sacubitril&#47;valsartan&#44; an angiotensin receptor-neprilysin inhibitor &#40;ARNI&#41;&#44; and standard chronic HF therapy with enalapril&#46; Sacubitril&#47;valsartan simultaneously modulates the natriuretic peptide system and the renin-angiotensin-aldosterone system&#44; a new approach in the treatment of chronic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> Sacubitril directly inhibits neprilysin&#44; a neutral endopeptidase that degrades various endogenous vasoactive substances including A&#44; B and C-type natriuretic peptides&#44; angiotensin &#40;hence the concomitant use of valsartan&#41;&#44; bradykinin and adrenomedullin&#46; The use of sacubitril&#47;valsartan therefore results in higher BNP levels&#44; although it has different affinities with BNP and NT-proBNP&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a> In vitro&#44; neprilysin cleaves B-type natriuretic peptide at various levels&#44; and the different assays used to determine serum BNP levels detect different epitopes&#44; with the result that serum BNP measurements can vary by 25&#37; depending on which epitopes are identified by the antibodies used in different reagents&#46; Since sacubitril&#47;valsartan affects all BNP assays&#44; it may do so in different proportions&#44; further complicating the interpretation of serum BNP levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">19&#44;20</span></a> Unlike BNP&#44; NT-proBNP is not a substrate for neprilysin&#44; so its levels are not directly affected by the drug&#39;s mechanism of action&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the PARADIGM-HF trial&#44; the use of sacubitril&#47;valsartan resulted in increases of about 10&#37; in BNP and of 90&#37; in urinary cGMP &#40;second messenger of BNP&#41;&#44; and a reduction in NT-proBNP&#44; in the short and medium term&#46; Recent data from the trial show that patients in whom NT-proBNP levels were reduced below 1000 pg&#47;ml had lower cardiovascular mortality and HF hospitalization rates regardless of the treatment arm to which they were allocated &#40;with a 59&#37; risk reduction compared to those in whom NT-proBNP levels did not decrease below 1000 pg&#47;dl&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> Sacubitril&#47;valsartan decreased NT-proBNP to levels below 1000 pg&#47;ml nearly twice as often as enalapril &#40;31&#37; vs&#46; 17&#37; of patients&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> These observations have made NT-proBNP the tool of choice for monitoring HF patients in clinical practice in the future&#46; The long-term behavior of BNP in patients under ARNI therapy is as yet unknown&#44; and there may even be further reductions in BNP levels&#44; but its potential for monitoring these patients will remain compromised&#46; In the authors&#8217; opinion&#44; clinicians should be knowledgeable and experienced in the use of one of the forms of B-type natriuretic peptide&#59; current knowledge indicates that NT-proBNP offers the best possibilities to the clinician in terms of clinical utility&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Recently&#44; research into this new drug class has indicated that soluble neprilysin is a potential new biomarker in acute and chronic HF&#44; and preliminary observations suggest it may be a more valuable prognostic marker than NT-proBNP&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">20&#8211;23</span></a> More research will be needed to test this hypothesis and to refine the reagents before this biomarker can be introduced into clinical practice&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Take-home messages</span><p id="par0030" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide &#40;BNP&#47;NT-proBNP&#41; is an important instrument in the diagnosis of HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide has prognostic value across the entire spectrum of HF severity&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical benefit of B-type natriuretic peptide for monitoring patients with HF is not yet proven&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Clinicians should be familiar with the use of one of the forms of B-type natriuretic peptide&#44; and currently NT-proBNP offers the most possibilities in terms of clinical utility&#46;</p></li></ul></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conflicts of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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            0 => "Heart failure"
            1 => "Natriuretic peptides"
            2 => "B-type natriuretic peptide"
            3 => "NT-proBNP"
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          "titulo" => "Palavras-chave"
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            0 => "Insufici&#234;ncia card&#237;aca"
            1 => "Pept&#237;deos natriureticos"
            2 => "BNP"
            3 => "NT-proBNP"
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        "titulo" => "Abstract"
        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Assessment of serum levels of natriuretic peptides&#44; especially the amino-terminal portion &#40;NT-proBNP&#41; and the carboxy-terminal portion &#40;BNP&#41; of pro-B-type natriuretic peptide&#44; has had a highly significant clinical impact on the diagnosis and prognostic stratification of patients with heart failure &#40;HF&#41;&#46; They are now an instrument with recognized value in this context and several studies have demonstrated their value in tailoring therapy for these patients&#46; Following the recent advent of angiotensin receptor-neprilysin inhibitors &#40;ARNIs&#41;&#44; there is a need to review how these two biomarkers are interpreted in HF&#46; The use of ARNIs is associated with a reduction in NT-proBNP but an increase in BNP levels&#46; The authors of this concise article review the interpretation of natriuretic peptide levels in the light of the most recent evidence&#46;</p></span>"
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        "titulo" => "Resumo"
        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">A determina&#231;&#227;o dos n&#237;veis s&#233;ricos de pept&#237;deos natriur&#233;ticos &#40;por&#231;&#227;o aminoterminal do pept&#237;deo natriur&#233;tico tipo B&#8211;NT-proBNP ou da por&#231;&#227;o carboxiterminal - BNP&#41; constituiu avan&#231;o cient&#237;fico com impacto cl&#237;nico muito relevante no diagn&#243;stico e na determina&#231;&#227;o progn&#243;stica de doentes com insufici&#234;ncia card&#237;aca &#40;IC&#41;&#46; S&#227;o hoje um instrumento com valor reconhecido nesse contexto e diversos estudos sugerem o seu interesse na titula&#231;&#227;o da terap&#234;utica desses doentes&#46; Recentemente&#44; com o conhecimento do valor terap&#234;utico do uso de inibidores da neprilisina&#47;antagonista dos recetores da angiotensina&#44; o uso desses dois biomarcadores na IC carece de interpreta&#231;&#227;o diversa&#46; O uso desses f&#225;rmacos associa-se &#224; redu&#231;&#227;o dos n&#237;veis de NT-proBNP mas a aumento dos n&#237;veis de BNP&#46; Os autores neste artigo conciso reveem a interpreta&#231;&#227;o e valoriza&#231;&#227;o dos n&#237;veis de pept&#237;dios natriur&#233;ticos &#224; luz da evid&#234;ncia mais recente&#46;</p></span>"
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        "etiqueta" => "&#9734;"
        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Bettencourt P&#44; Fonseca C&#44; Franco F&#44; et al&#46; Interpreta&#231;&#227;o dos peptideos natriur&#233;ticos tipo B na era dos antagonistas da neprilisina&#47;recetores da angiotensina &#40;ARNIs&#41;&#46; Rev Port Cardiol&#46; 2017&#59;36&#58;881&#8211;884&#46;</p>"
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Perspectives in Cardiology
Interpretation of B-type natriuretic peptides in the era of angiotensin receptor-neprilysin inhibitors
Interpretação dos peptídeos natriuréticos tipo B na era dos antagonistas da neprilisina/recetores da angiotensina (ARNIs)
Paulo Bettencourta,
Corresponding author
pbettfer@med.up.pt

Corresponding author.
, Cândida Fonsecab, Fátima Francoc, Aurora Andraded, Dulce Britoe
a Faculdade de Medicina UP, Hospital CUF Porto, Porto, Portugal
b Unidade de Insuficiência Cardíaca, Serviço de Medicina III, H. S. Francisco Xavier, CHLO, NOVA Medical School, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, Lisboa, Portugal
c Unidade Tratamento IC Avançada (UTICA), Serviço de Cardiologia, Centro Hospitalar Universitário de Coimbra, Coimbra, Portugal
d Serviço Cardiologia, Hospital Tâmega e Vale Sousa, Penafiel, Portugal
e Serviço de Cardiologia, CHLN, CCUL, Centro Académico de Medicina de Lisboa, Faculdade de Medicina da Universidade de Lisboa, Lisboa, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">Since the end of the 20th century there has been an explosion of clinical research on biomarkers in heart failure &#40;HF&#41;&#44; particularly B-type natriuretic peptide&#46; The value of this biomarker in the diagnosis of HF&#44; particularly acute HF&#44; is now clear&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">1</span></a> Assessment of the carboxy-terminal portion &#40;BNP&#41; and the amino-terminal portion &#40;NT-proBNP&#41; of B-type natriuretic peptide enables clinicians to determine the mechanism associated with dyspnea&#58; HF&#44; when elevated or of non-cardiac cause&#59; and pulmonary disease when low&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">2&#44;3</span></a> The diagnostic value of B-type natriuretic peptide is now recognized to be even greater when there is a high degree of uncertainty concerning the mechanism underlying dyspnea in the acute patient&#46;<a class="elsevierStyleCrossRef" href="#bib0135"><span class="elsevierStyleSup">4</span></a> This instrument is available in most emergency departments in Portugal and it will be a challenge to evaluate its cost-effectiveness in the Portuguese health system&#46; In other health systems&#44; its clinical value&#44; including cost-effectiveness&#44; has been clearly demonstrated&#46;<a class="elsevierStyleCrossRefs" href="#bib0140"><span class="elsevierStyleSup">5&#44;6</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The prognostic value of B-type natriuretic peptide is also recognized across the spectrum of HF severity&#44; in both acute and chronic patients&#46;<a class="elsevierStyleCrossRefs" href="#bib0150"><span class="elsevierStyleSup">7&#8211;9</span></a> Variations in its levels are significantly associated with prognosis<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#44;11</span></a>&#58; patients with higher levels despite optimization of therapy have a significantly worse prognosis than those with large &#40;&#62;30&#37;&#41; reductions&#46;<a class="elsevierStyleCrossRefs" href="#bib0165"><span class="elsevierStyleSup">10&#8211;14</span></a> These observations prompted various trials that set out to assess whether B-type natriuretic peptide levels were a valid target for evaluating the efficacy of treatment of HF patients&#46; Another motive for these trials was the observation that therapies associated with prognostic improvement were linked to reductions in B-type natriuretic peptide levels &#40;except for adrenergic blockers&#44; which are associated with medium-term reductions only&#41;&#46; The conclusions of these trials &#40;10 to date&#41; have been conflicting&#44;<a class="elsevierStyleCrossRefs" href="#bib0190"><span class="elsevierStyleSup">15&#44;16</span></a> and differences in study design&#44; target B-type natriuretic peptide levels and the methods used to achieve them hinder accurate interpretation of the results&#46; However&#44; all these trials have some points in common&#58; therapy aimed at reducing B-type natriuretic peptide levels was not associated with a higher incidence of adverse effects&#44; and natriuretic peptide-guided therapy appears to be of more benefit in patients aged under 75 years&#46; When interpreting these biomarkers&#44; it is also important to identify patients in whom modulation of the natriuretic peptide system will be more difficult due to &#8216;ventricular exhaustion&#8217; &#40;pathophysiological inability to synthesize and secrete natriuretic peptides&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">17</span></a> Although these trials do not show decisively that modulation of natriuretic peptides is the way forward for the individualized treatment of HF patients&#44; it still has considerable potential and hence remains under investigation&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">The medical world was recently startled by the results of a study &#40;PARADIGM-HF&#41; that compared sacubitril&#47;valsartan&#44; an angiotensin receptor-neprilysin inhibitor &#40;ARNI&#41;&#44; and standard chronic HF therapy with enalapril&#46; Sacubitril&#47;valsartan simultaneously modulates the natriuretic peptide system and the renin-angiotensin-aldosterone system&#44; a new approach in the treatment of chronic HF&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">18</span></a> Sacubitril directly inhibits neprilysin&#44; a neutral endopeptidase that degrades various endogenous vasoactive substances including A&#44; B and C-type natriuretic peptides&#44; angiotensin &#40;hence the concomitant use of valsartan&#41;&#44; bradykinin and adrenomedullin&#46; The use of sacubitril&#47;valsartan therefore results in higher BNP levels&#44; although it has different affinities with BNP and NT-proBNP&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">19</span></a> In vitro&#44; neprilysin cleaves B-type natriuretic peptide at various levels&#44; and the different assays used to determine serum BNP levels detect different epitopes&#44; with the result that serum BNP measurements can vary by 25&#37; depending on which epitopes are identified by the antibodies used in different reagents&#46; Since sacubitril&#47;valsartan affects all BNP assays&#44; it may do so in different proportions&#44; further complicating the interpretation of serum BNP levels&#46;<a class="elsevierStyleCrossRefs" href="#bib0210"><span class="elsevierStyleSup">19&#44;20</span></a> Unlike BNP&#44; NT-proBNP is not a substrate for neprilysin&#44; so its levels are not directly affected by the drug&#39;s mechanism of action&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">In the PARADIGM-HF trial&#44; the use of sacubitril&#47;valsartan resulted in increases of about 10&#37; in BNP and of 90&#37; in urinary cGMP &#40;second messenger of BNP&#41;&#44; and a reduction in NT-proBNP&#44; in the short and medium term&#46; Recent data from the trial show that patients in whom NT-proBNP levels were reduced below 1000 pg&#47;ml had lower cardiovascular mortality and HF hospitalization rates regardless of the treatment arm to which they were allocated &#40;with a 59&#37; risk reduction compared to those in whom NT-proBNP levels did not decrease below 1000 pg&#47;dl&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> Sacubitril&#47;valsartan decreased NT-proBNP to levels below 1000 pg&#47;ml nearly twice as often as enalapril &#40;31&#37; vs&#46; 17&#37; of patients&#44; respectively&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">14</span></a> These observations have made NT-proBNP the tool of choice for monitoring HF patients in clinical practice in the future&#46; The long-term behavior of BNP in patients under ARNI therapy is as yet unknown&#44; and there may even be further reductions in BNP levels&#44; but its potential for monitoring these patients will remain compromised&#46; In the authors&#8217; opinion&#44; clinicians should be knowledgeable and experienced in the use of one of the forms of B-type natriuretic peptide&#59; current knowledge indicates that NT-proBNP offers the best possibilities to the clinician in terms of clinical utility&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall">Recently&#44; research into this new drug class has indicated that soluble neprilysin is a potential new biomarker in acute and chronic HF&#44; and preliminary observations suggest it may be a more valuable prognostic marker than NT-proBNP&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">20&#8211;23</span></a> More research will be needed to test this hypothesis and to refine the reagents before this biomarker can be introduced into clinical practice&#46;</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Take-home messages</span><p id="par0030" class="elsevierStylePara elsevierViewall"><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0035" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide &#40;BNP&#47;NT-proBNP&#41; is an important instrument in the diagnosis of HF&#46;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0040" class="elsevierStylePara elsevierViewall">B-type natriuretic peptide has prognostic value across the entire spectrum of HF severity&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0045" class="elsevierStylePara elsevierViewall">The clinical benefit of B-type natriuretic peptide for monitoring patients with HF is not yet proven&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0050" class="elsevierStylePara elsevierViewall">Clinicians should be familiar with the use of one of the forms of B-type natriuretic peptide&#44; and currently NT-proBNP offers the most possibilities in terms of clinical utility&#46;</p></li></ul></p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Conflicts of interest</span><p id="par0055" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare&#46;</p></span></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="npar0005">Please cite this article as&#58; Bettencourt P&#44; Fonseca C&#44; Franco F&#44; et al&#46; Interpreta&#231;&#227;o dos peptideos natriur&#233;ticos tipo B na era dos antagonistas da neprilisina&#47;recetores da angiotensina &#40;ARNIs&#41;&#46; Rev Port Cardiol&#46; 2017&#59;36&#58;881&#8211;884&#46;</p>"
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ISSN: 21742049
Original language: English
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Revista Portuguesa de Cardiologia (English edition)
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