Editorial comment
Medical therapy for heart failure with preserved ejection fraction: Still a minefield, but with new hope
Terapêutica médica na insuficiência cardíaca com fração de ejeção preservada: ainda um campo minado, mas com novas esperanças!
Matteo Pagnesi, Antonio M. Sammartino, Marco Metra
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Institute of Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy
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MiR-223-3p has been associated with several carcinomas, and is involved in cell proliferation, growth, migration and invasion, furthermore it negatively regulates PRDM1 involved in immune and inflammatory processes. KLF15 promotes cellular growth, regulating negatively TGFβ1 and RASA1, promoting cell migration.<a class="elsevierStyleCrossRefs" href="#bib0720"><span class="elsevierStyleSup">67–70</span></a> MiR-21 is negatively related to TGFβ1/SMAD7 and TNFα1, enhancing fibrotic processes, thus promoting ventricular remodeling.<a class="elsevierStyleCrossRefs" href="#bib0740"><span class="elsevierStyleSup">71–73</span></a> Let-7i-5p is known for negatively regulating inflammation and fibrosis processes, partly due to its effect on Ang-II and IL-6 and on E2F2 and CCND2 expression (regulators of cell cycle) and cardiac recovery.<a class="elsevierStyleCrossRefs" href="#bib0630"><span class="elsevierStyleSup">49,74</span></a> Few studies analysed miR-1254 targets, which is thought to be involved in cardiac remodeling, playing a protective role by inhibiting the PI3K/AKT pathway and SMURF1 expression (important in cell motility, signaling and polarity processes).<a class="elsevierStyleCrossRef" href="#bib0760"><span class="elsevierStyleSup">75</span></a> MiR-106-5p might have a protective role, since it is suggested that it affects stress response due to MAPK signaling pathway inhibition and consequently oxidative stress.<a class="elsevierStyleCrossRefs" href="#bib0765"><span class="elsevierStyleSup">76,77</span></a> MiR-1306-3p inhibits the TGFβ/SMAD pathway, and is involved in pro-apoptotic processes. MiR-423-3p expression is triggered by hypoxia/reoxygenation processes, positively regulating Caspase 3/7, Bax, Caspase C promoting mitochondrial dysfunction.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Rita Figueiredo, Rui Adão, Adelino F. Leite-Moreira, Jennifer Mâncio, Carmen Brás-Silva" "autores" => array:5 [ 0 => array:2 [ "nombre" => "Rita" "apellidos" => "Figueiredo" ] 1 => array:2 [ "nombre" => "Rui" "apellidos" => "Adão" ] 2 => array:2 [ "nombre" => "Adelino F." "apellidos" => "Leite-Moreira" ] 3 => array:2 [ "nombre" => "Jennifer" "apellidos" => "Mâncio" ] 4 => array:2 [ "nombre" => "Carmen" "apellidos" => "Brás-Silva" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122002797?idApp=UINPBA00004E" "url" => "/08702551/0000004100000010/v1_202210061538/S0870255122002797/v1_202210061538/en/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S0870255122002761" "issn" => "08702551" "doi" => "10.1016/j.repc.2021.06.027" "estado" => "S300" "fechaPublicacion" => "2022-10-01" "aid" => "1996" "copyright" => "Sociedade Portuguesa de Cardiologia" "documento" => "article" "crossmark" => 1 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/4.0/" "subdocumento" => "fla" "cita" => "Rev Port Cardiol. 2022;41:853-61" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:1 [ "total" => 0 ] "en" => array:13 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Original Article</span>" "titulo" => "Beta-blocker use in patients with heart failure with preserved ejection fraction and sinus rhythm" "tienePdf" => "en" "tieneTextoCompleto" => "en" "tieneResumen" => array:2 [ 0 => "en" 1 => "pt" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "853" "paginaFinal" => "861" ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Utilização de betabloqueantes em doentes com insuficiência cardíaca com fração de ejeção preservada e em ritmo sinusal" ] ] "contieneResumen" => array:2 [ "en" => true "pt" => true ] "contieneTextoCompleto" => array:1 [ "en" => true ] "contienePdf" => array:1 [ "en" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1564 "Ancho" => 1752 "Tamanyo" => 91315 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">Kaplan-Meier survival curve for all-cause mortality at one year according to discharge beta-blocker prescription. Log-rank p=0.235.</p>" ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Francesc Formiga, David Chivite, Julio Nuñez, Ma Carmen Moreno García, Luis Manzano, José Carlos Arévalo-Lorido, Jose Manuel Cerqueiro, Álvaro García Campos, Joan Carles Trullàs, Manuel Montero-Pérez-Barquero" "autores" => array:11 [ 0 => array:2 [ "nombre" => "Francesc" "apellidos" => "Formiga" ] 1 => array:2 [ "nombre" => "David" "apellidos" => "Chivite" ] 2 => array:2 [ "nombre" => "Julio" "apellidos" => "Nuñez" ] 3 => array:2 [ "nombre" => "Ma Carmen" "apellidos" => "Moreno García" ] 4 => array:2 [ "nombre" => "Luis" "apellidos" => "Manzano" ] 5 => array:2 [ "nombre" => "José Carlos" "apellidos" => "Arévalo-Lorido" ] 6 => array:2 [ "nombre" => "Jose Manuel" "apellidos" => "Cerqueiro" ] 7 => array:2 [ "nombre" => "Álvaro" "apellidos" => "García Campos" ] 8 => array:2 [ "nombre" => "Joan Carles" "apellidos" => "Trullàs" ] 9 => array:2 [ "nombre" => "Manuel" "apellidos" => "Montero-Pérez-Barquero" ] 10 => array:1 [ "colaborador" => "on behalf of the RICA Investigators group" ] ] ] ] ] "idiomaDefecto" => "en" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S0870255122002761?idApp=UINPBA00004E" "url" => "/08702551/0000004100000010/v1_202210061538/S0870255122002761/v1_202210061538/en/main.assets" ] "en" => array:12 [ "idiomaDefecto" => true "cabecera" => "<span class="elsevierStyleTextfn">Editorial comment</span>" "titulo" => "Medical therapy for heart failure with preserved ejection fraction: Still a minefield, but with new hope" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "863" "paginaFinal" => "864" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Matteo Pagnesi, Antonio M. Sammartino, Marco Metra" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Matteo" "apellidos" => "Pagnesi" ] 1 => array:2 [ "nombre" => "Antonio M." "apellidos" => "Sammartino" ] 2 => array:4 [ "nombre" => "Marco" "apellidos" => "Metra" "email" => array:1 [ 0 => "metramarco@libero.it" ] "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] ] "afiliaciones" => array:1 [ 0 => array:2 [ "entidad" => "Institute of Cardiology, ASST Spedali Civili, Department of Medical and Surgical Specialties, Radiological Sciences and Public Health, University of Brescia, Brescia, Italy" "identificador" => "aff0005" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Terapêutica médica na insuficiência cardíaca com fração de ejeção preservada: ainda um campo minado, mas com novas esperanças!" ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="par0005" class="elsevierStylePara elsevierViewall">In this issue of the <span class="elsevierStyleItalic">Journal</span>, Formiga et al. present an analysis of the Spanish multicenter prospective RICA registry assessing the impact of beta-blocker therapy prescribed at discharge in a cohort of 1078 elderly patients with heart failure (HF) with preserved ejection fraction (HFpEF) who were admitted for acute HF and were in sinus rhythm at hospital admission.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> In brief, the national RICA registry, coordinated by the Heart Failure Working Group of the Spanish Society of Internal Medicine, enrolled consecutive patients admitted for acute HF to internal medicine wards at 52 Spanish hospitals. In this study, use of beta-blockers at discharge was not associated with a lower risk of one-year all-cause mortality (adjusted hazard ratio [HR] 0.83; 95% confidence interval [CI] 0.61-1.13; p=0.236) or of the one-year composite endpoint of all-cause death or HF rehospitalization (adjusted HR 0.98; 95% CI 0.79-1.23; p=0.882) in patients with acute HFpEF and sinus rhythm.<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">1</span></a> The strengths of this study are the prospective and multicenter design of the real-world RICA registry and its large sample size. The main limitation is the observational nature of the study, which was potentially affected by residual unmeasured or confounding bias despite the adjusted analyses that were performed by the authors.</p><p id="par0010" class="elsevierStylePara elsevierViewall">The results of this study are in line with available evidence demonstrating the lack of benefit of beta-blockers in HFpEF. In a large individual patient data meta-analysis of 10 trials including 18 254 patients with HF, the benefit of beta-blocker therapy versus placebo in terms of reduction in all-cause mortality was observed only in patients in sinus rhythm, and not in those with atrial fibrillation.<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">2</span></a> In a subsequent large individual patient data meta-analysis of 11 trials including 14 262 patients with HF and in sinus rhythm, beta-blockers improved left ventricular ejection fraction (LVEF) and prognosis in patients with HF with reduced ejection fraction (HFrEF), but not in those with HFpEF.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> Use of beta-blockers reduced all-cause or cardiovascular mortality compared to placebo only in patients with LVEF <40% and in those with LVEF 40-49%.<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">3</span></a> Although the non-randomized observational design of this study prevents definitive conclusions from being drawn, Formiga et al. also confirmed these findings in a real-world population of patients who were hospitalized for acute HF and had evidence of HFpEF and sinus rhythm.</p><p id="par0015" class="elsevierStylePara elsevierViewall">Considering the high burden of comorbidities in patients with HFpEF, including atrial fibrillation, chronic kidney disease, obesity, and other non-cardiovascular comorbidities that are more common in HFpEF than in HFrEF,<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">4,5</span></a> focusing on the treatment of comorbidities remains of paramount importance in these patients. In the absence of robust evidence from available randomized trials supporting a prognostic benefit of most HFrEF drugs in the treatment of HFpEF, the recent European Society of Cardiology guidelines for the diagnosis and treatment of acute and chronic HF recommend reducing symptoms and signs of congestion with diuretics and treating cardiovascular and non-cardiovascular comorbidities, including hypertension, obesity, coronary artery disease, amyloidosis, atrial fibrillation and valvular heart disease, in patients with HFpEF.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> Beta-blockers therefore remain a relevant therapeutic option for the treatment of comorbidities in patients with HFpEF, such as hypertension or coronary artery disease.<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">Of note, after several randomized trials conducted in HFpEF failed to achieve their primary endpoints,<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">6</span></a> the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction (EMPEROR-Preserved) and the Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure (SOLOIST-WHF) trials have recently reported positive results in these patients.<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">7,8</span></a> SOLOIST-WHF, however, enrolled only diabetic patients hospitalized for HF.<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">8</span></a> By contrast, EMPEROR-Preserved enrolled diabetic and non-diabetic patients with HF and New York Heart Association class II to IV symptoms and increased N-terminal pro-B-type natriuretic peptide levels.<a class="elsevierStyleCrossRefs" href="#bib0085"><span class="elsevierStyleSup">5,7</span></a> In EMPEROR-Preserved, the sodium-glucose cotransporter 2 inhibitor empagliflozin led to a significant 21% reduction in the primary composite endpoint of cardiovascular death or HF hospitalization in 5988 patients with HF and LVEF >40% (mean LVEF 54.3%), regardless of the presence or absence of diabetes.<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">7</span></a> This positive trial has raised the real possibility of finding a treatment for all patients with HFpEF, in fact for all patients with HF, independently of LVEF.<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">9</span></a> Beyond the use of gliflozins, detailed phenotyping, treatment of comorbidities and personalized patient approaches remain the mainstay of treatment in HFpEF. Machine learning techniques and identification of phenotype clusters are not often advocated as tools to better characterize patients with HFpEF.<a class="elsevierStyleCrossRefs" href="#bib0110"><span class="elsevierStyleSup">10–12</span></a> Further progress in our understanding of the pathophysiology of HFpEF is now required to refine HFpEF management and potentially find more effective medical therapies for this challenging and difficult-to-treat patient population.</p><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Conflicts of interest</span><p id="par0025" class="elsevierStylePara elsevierViewall">Prof. Metra received personal consulting honoraria from Abbott, Amgen, Bayer, Edwards Therapeutics, LivaNova and Vifor Pharma for participation to advisory board meetings and executive committees of clinical trials. All the other authors have no conflicts of interest to declare.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:2 [ 0 => array:2 [ "identificador" => "sec0005" "titulo" => "Conflicts of interest" ] 1 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:12 [ 0 => array:3 [ "identificador" => "bib0065" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Beta-blocker use in patients with heart failure with preserved ejection fraction and sinus rhythm" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "F. Formiga" 1 => "D. Chivite" 2 => "J. Nuñez" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Rev Port Cardiol" "fecha" => "2022" "volumen" => "41" "paginaInicial" => "853" "paginaFinal" => "861" ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0070" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Efficacy of β blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:3 [ 0 => "D. Kotecha" 1 => "J. Holmes" 2 => "H. 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| Ano/Mês | Html | Total | |
|---|---|---|---|
| 2024 Novembro | 8 | 8 | 16 |
| 2024 Outubro | 38 | 21 | 59 |
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| 2024 Julho | 43 | 28 | 71 |
| 2024 Junho | 33 | 27 | 60 |
| 2024 Maio | 28 | 12 | 40 |
| 2024 Abril | 45 | 17 | 62 |
| 2024 Maro | 41 | 20 | 61 |
| 2024 Fevereiro | 26 | 18 | 44 |
| 2024 Janeiro | 28 | 22 | 50 |
| 2023 Dezembro | 24 | 24 | 48 |
| 2023 Novembro | 19 | 17 | 36 |
| 2023 Outubro | 24 | 23 | 47 |
| 2023 Setembro | 18 | 16 | 34 |
| 2023 Agosto | 16 | 13 | 29 |
| 2023 Julho | 28 | 10 | 38 |
| 2023 Junho | 35 | 8 | 43 |
| 2023 Maio | 31 | 29 | 60 |
| 2023 Abril | 22 | 3 | 25 |
| 2023 Maro | 38 | 20 | 58 |
| 2023 Fevereiro | 24 | 18 | 42 |
| 2023 Janeiro | 25 | 11 | 36 |
| 2022 Dezembro | 43 | 31 | 74 |
| 2022 Novembro | 79 | 53 | 132 |
| 2022 Outubro | 133 | 74 | 207 |
| 2022 Setembro | 41 | 40 | 81 |
| 2022 Agosto | 27 | 27 | 54 |
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