Letter to the Editor
When sacubitril/valsartan met neprilysin and B-type natriuretic peptide in the labyrinth of biochemistry
Quando o sacubitril/valsartan encontra a neprilisina e o peptídeo natriurético auricular tipo B no labirinto da bioquímica
Eftychios Siniorakisa, Spyridon Arvanitakisa,
, Maximilianos Elkourisb, Efstratios Katsianosc, Panayotis Pelonisa, Antonia Tertipia
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a Heart Failure Clinic, Sotiria Chest Diseases Hospital, 152 Mesogeion Avenue, 11527 Athens, Greece
b Clinical Biochemistry Department, Sotiria Chest Diseases Hospital, 152 Mesogeion Avenue, 11527 Athens, Greece
c 3rd University Cardiology Department, Sotiria Chest Diseases Hospital, 152 Mesogeion Avenue, 11527 Athens, Greece
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"etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Quando o sacubitril/valsartan encontra a neprilisina e o peptídeo natriurético auricular tipo B no labirinto da bioquímica" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">We read with interest the article by Fonseca and colleagues, which provides a practical guide on sacubitril/valsartan (SV).<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">1</span></a> We noted that in accordance with the suggestions of the PARADIGM-HF study, the authors discourage the use of B-type natriuretic peptide (BNP) in monitoring the effectiveness of SV during heart failure (HF) treatment.<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">2</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">SV is at the same time an angiotensin receptor blocker and a neprilysin (NEP) inhibitor. NEP is a metalloprotease that catalyzes several peptides, including BNP. Inhibition of NEP by SV is expected to cause a transient increase in BNP, giving the erroneous impression of failed treatment. To avoid misinterpretations, PARADIGM-HF proposes the exclusive use of the terminal form NT-proBNP, which is resistant to NEP, instead of BNP. The novel drug SV is expanding worldwide as a promising and revolutionary treatment in the previously stagnant environment of pharmaceutical HF treatment. However, the establishment of SV threatens BNP as a diagnostic and prognostic biomarker.</p><p id="par0015" class="elsevierStylePara elsevierViewall">BNP is a well-established biomarker of HF, with significant diagnostic and prognostic properties. It is secreted during myocardial stress and promotes diuresis and vasodilatation while expressing anti-fibrotic and anti-inflammatory characteristics. Furthermore, BNP inhibits the renin-angiotensin-aldosterone system and regulates cardiorenal interactions. The precursor of BNP is proBNP, which when split also forms the inactive terminal form NT-proBNP. NT-proBNP and BNP are used interchangeably as biomarkers in clinical practice, and have been used extensively in recent decades in modern cardiology.<a class="elsevierStyleCrossRef" href="#bib0060"><span class="elsevierStyleSup">3</span></a> Before sending BNP into exile, its complex relationship with NEP should be reviewed from a laboratory point of view, in biochemical terms.</p><p id="par0020" class="elsevierStylePara elsevierViewall">Only immunoreactive forms of BNP are assessed by common commercial assays, which contain monoclonal or polyclonal antibodies targeting specific epitopes.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">4</span></a> Immunoreactive BNP is conjugated to proBNP, so both forms are inseparably included in the final result.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> In humans, the proBNP-BNP complex is a poor substrate for NEP, which cleaves only a limited number of bonds, depending on the type of assay used.<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">6,7</span></a> Apart from NEP, the proBNP-BNP complex is also degraded by other exogenous and endogenous proteases including insulin-degrading enzyme, proteases of the kallikrein family and natriuretic peptide receptors of the guanylate cyclase family.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">5</span></a> All these catalysts remain unaffected by the inhibitory action of SV on NEP, and therefore do not provoke a drug-mediated change in BNP.</p><p id="par0025" class="elsevierStylePara elsevierViewall">Interestingly, human BNP itself is a NEP inhibitor. Recently, in vitro as well as in vivo, it was found that BNP values >900 pg/ml degrade NEP decisively.<a class="elsevierStyleCrossRef" href="#bib0085"><span class="elsevierStyleSup">8</span></a> In this light, the methodology of PARADIGM-HF should be re-evaluated. The majority of enrolled patients were in NYHA class II, with average BNP values of 255 pg/ml. In these patients NEP is expected to be overactive, prone to be catalyzed by SV. In NYHA III and IV patients, higher values of BNP seem to be involved in reduced NEP activity, raising questions about SV's further synergistic action.</p><p id="par0030" class="elsevierStylePara elsevierViewall">The complex relationship between BNP and NEP is not amenable to simplifications. The results of PARADIGM-HF concerning the validity of BNP may be reconsidered after a thorough re-exploration of the study methodology from a biochemical point of view. The concept of HF is currently moving from the classic renin-angiotensin-aldosterone system theory to the context of proteases and their substrates. Withdrawing BNP from the investigation of these novel mechanisms is a challenge we should not surrender to. In the meanwhile appropriate algorithms for estimating the dynamic of natriuretic peptides in HF treated with SV are awaited with considerable interest.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">9</span></a></p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Funding</span><p id="par0035" class="elsevierStylePara elsevierViewall">No funding was received for the preparation of this manuscript.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Conflicts of interest</span><p id="par0040" class="elsevierStylePara elsevierViewall">The authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Funding" ] 1 => array:2 [ "identificador" => "sec0010" "titulo" => "Conflicts of interest" ] 2 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:9 [ 0 => array:3 [ "identificador" => "bib0050" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Sacubitril/valsartan: a practical guide" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "C. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 11 | 8 | 19 |
| 2024 Outubro | 37 | 28 | 65 |
| 2024 Setembro | 48 | 28 | 76 |
| 2024 Agosto | 52 | 37 | 89 |
| 2024 Julho | 43 | 31 | 74 |
| 2024 Junho | 39 | 27 | 66 |
| 2024 Maio | 36 | 18 | 54 |
| 2024 Abril | 42 | 29 | 71 |
| 2024 Maro | 27 | 24 | 51 |
| 2024 Fevereiro | 24 | 28 | 52 |
| 2024 Janeiro | 28 | 28 | 56 |
| 2023 Dezembro | 17 | 29 | 46 |
| 2023 Novembro | 29 | 32 | 61 |
| 2023 Outubro | 29 | 21 | 50 |
| 2023 Setembro | 28 | 18 | 46 |
| 2023 Agosto | 18 | 20 | 38 |
| 2023 Julho | 36 | 13 | 49 |
| 2023 Junho | 28 | 14 | 42 |
| 2023 Maio | 34 | 27 | 61 |
| 2023 Abril | 17 | 2 | 19 |
| 2023 Maro | 49 | 23 | 72 |
| 2023 Fevereiro | 48 | 19 | 67 |
| 2023 Janeiro | 11 | 19 | 30 |
| 2022 Dezembro | 22 | 21 | 43 |
| 2022 Novembro | 44 | 27 | 71 |
| 2022 Outubro | 39 | 20 | 59 |
| 2022 Setembro | 23 | 26 | 49 |
| 2022 Agosto | 24 | 26 | 50 |
| 2022 Julho | 25 | 46 | 71 |
| 2022 Junho | 20 | 29 | 49 |
| 2022 Maio | 21 | 30 | 51 |
| 2022 Abril | 31 | 26 | 57 |
| 2022 Maro | 26 | 30 | 56 |
| 2022 Fevereiro | 19 | 29 | 48 |
| 2022 Janeiro | 15 | 29 | 44 |
| 2021 Dezembro | 26 | 27 | 53 |
| 2021 Novembro | 19 | 32 | 51 |
| 2021 Outubro | 47 | 53 | 100 |
| 2021 Setembro | 28 | 39 | 67 |
| 2021 Agosto | 34 | 35 | 69 |
| 2021 Julho | 20 | 17 | 37 |
| 2021 Junho | 17 | 20 | 37 |
| 2021 Maio | 23 | 37 | 60 |
| 2021 Abril | 16 | 48 | 64 |
| 2021 Maro | 25 | 13 | 38 |
| 2021 Fevereiro | 29 | 13 | 42 |
| 2021 Janeiro | 33 | 20 | 53 |
| 2020 Dezembro | 38 | 21 | 59 |
| 2020 Novembro | 24 | 23 | 47 |
| 2020 Outubro | 28 | 12 | 40 |
| 2020 Setembro | 31 | 17 | 48 |
| 2020 Agosto | 7 | 16 | 23 |
| 2020 Julho | 31 | 15 | 46 |
| 2020 Junho | 35 | 25 | 60 |
| 2020 Maio | 71 | 42 | 113 |
| 2020 Abril | 17 | 17 | 34 |
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