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© 2021 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) with reduced ejection fraction (HFrEF) is associated with high rates of hospitalization and death. It also has a negative impact on patients' functional capacity and quality of life, as well as on healthcare costs. In recent years, new HFrEF prognosis-modifying drugs have emerged, leading to intense debate within the international scientific community toward a paradigm shift for the management of HFrEF. In this article, we report the contribution of a Portuguese HF expert panel to the ongoing debate. Based on the most recently published clinical evidence, and the panel members' clinical judgment, three key principles are highlighted: (i) sacubitril/valsartan should be preferred as first-line therapy for HFrEF, instead of an angiotensin-converting enzyme inhibitor or angiotensin receptor blocker; (ii) the four foundation HFrEF drugs are the angiotensin receptor/neprilysin inhibitor, beta-adrenergic blocking agents, mineralocorticoid receptor antagonists, and sodium-glucose co-transporter 2 inhibitors, regardless of the presence of type-2 diabetes mellitus; (iii) these four HFrEF drug classes should be introduced over a short-term period of four to six weeks, guided by a safety protocol, followed by a dose up-titration period of 8 weeks., A insuficiência cardíaca (IC) com fração de ejeção reduzida (ICFEr) está associada a níveis elevados de hospitalização e mortalidade. A ICFEr também tem um impacto negativo na capacidade funcional e na qualidade de vida dos doentes, bem como na despesa em saúde. Nos últimos anos, surgiram novos medicamentos modificadores do prognóstico da ICFEr, originando um intenso debate na comunidade científica internacional em relação a uma mudança de paradigma para o tratamento da ICFEr. Neste artigo, relatamos a contribuição de um painel de especialistas portugueses em IC para o debate em curso. Com base na evidência clínica publicada mais recentemente e no julgamento clínico dos membros do painel, três princípios-chave são destacados: (i) sacubitril/valsartan deve ser preferido como terapia de primeira linha para a ICFEr, em vez de um inibidor da enzima de conversão da angiotensina ou um bloqueador do recetor da angiotensina; (ii) os quatro medicamentos básicos para a ICFEr são o inibidor do recetor da angiotensina e da neprilisina, os agentes bloqueadores beta-adrenérgicos, os antagonistas do recetor mineralocorticoide e os inibidores do cotransportador sódio-glucose 2, independentemente da presença de diabetes mellitus tipo 2; (iii) essas quatro classes de medicamentos para a ICFEr devem ser rapidamente introduzidas num período curto de 4-6 semanas, seguindo um protocolo de segurança, e depois tituladas durante as oito semanas seguintes.

Background and aim Frailty Phenotype (FP) is very common in Heart Failure (HF) and both syndromes worsen one another. The aim of this study is to first describe FP in a sample of Portuguese HF patients, and to analyse its association with nutritional and clinical statuses, namely muscle mass, obesity and functional class. Methods and results In this cross-sectional study, a sample of 136 heart failure outpatients (24-81 years, 33.8% women) was randomly selected from the appointments’ listings of a HF and Transplant clinic in a Portuguese University Hospital. FP was assessed according to Fried et al.; muscle mass was estimated from mid-upper arm muscle circumference; weight status was assessed using body mass index; HF functional classes were registered. The association between participants’ characteristics and FP categories was analysed using logistic ordinal regression. The frequency of pre-frailty and frailty is 57.4% and 15.4%, respectively. Within frail individuals, 52.4% were under the age of 65. In multivariable analysis, frailty was positively associated with being 70 or older (OR = 3.44) and obese (OR = 2.66), and negatively associated with muscle mass (OR = 0.77) and with being at class I (OR = 0.14) or class II (OR = 0.29) of HF functional classes. Conclusion Muscle mass seems to be an important predictor of frailty in HF patients and should be taken into account when designing intervention plans that allow for reverting or modifying frailty and pre-frailty. Younger patients should be monitored for the presence and evolution of FP.

Background: Inflammatory responses play an important role in the pathophysiology of cardiogenic shock (CS). The aim of this study was to investigate the kinetics of procalcitonin (PCT), C-reactive protein (CRP), and interleukin-6 (IL-6) in CS and to assess their relation to clinical presentation, other biochemical variables, and prognosis. Methods: Levels of PCT, CRP and IL-6 were analyzed in serial plasma samples (0-120h) from 183 patients in the CardShock study. The study population was dichotomized by PCTmax >= and < 0.5 mu g/L, and IL-6 and CRPmax above/below median. Results: PCT peaked already at 24 h [median PCTmax 0.71 mu g/L (IQR 0.24-3.4)], whereas CRP peaked later between 48 and 72 h [median CRPmax 137mg/L (59-247)]. PCT levels were significantly higher among non-survivors compared with survivors from 12 h on, as were CRP levels from 24 h on (p < 0.001). PCTmax >= 0.5 mu g/L (60% of patients) was associated with clinical signs of systemic hypoperfusion, cardiac and renal dysfunction, acidosis, and higher levels of blood lactate, IL-6, growth-differentiation factor 15 (GDF-15), and CRPmax. Similarly, IL-6 > median was associated with clinical signs and biochemical findings of systemic hypoperfusion. PCTmax >= 0.5 mu g/L and IL-6 > median were associated with increased 90-day mortality (50% vs. 30% and 57% vs. 22%, respectively; p < 0.01 for both), while CRPmax showed no prognostic significance. The association of inflammatory markers with clinical infections was modest. Conclusions: Inflammatory markers are highly related to signs of systemic hypoperfusion in CS. Moreover, high PCT and IL-6 levels are associated with poor prognosis. (C) 2020 Elsevier B.V. All rights reserved.

© The Author(s) 2020, Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are a new drug class designed to treat patients with type 2 diabetes (T2D). However, cardiovascular outcome trials showed that SGLT2i also offer protection against heart failure (HF)–related events and cardiovascular mortality. These benefits appear to be independent of glycaemic control and have recently been demonstrated in the HF population with reduced ejection fraction (HFrEF), with or without T2D. This comprehensive, evidence-based review focuses on the published studies concerning HF outcomes with SGLT2i, discussing issues that may underlie the different results, along with the impact of these new drugs in clinical practice. The potential translational mechanisms behind SGLT2i cardio-renal benefits and the information that ongoing studies may add to the already existing body of evidence are also reviewed. Finally, we focus on practical management issues regarding SGLT2i use in association with other T2D and HFrEF common pharmacological therapies. Safety considerations are also highlighted. Considering the paradigm shift in T2D management, from a focus on glycaemic control to a broader approach on cardiovascular protection and event reduction, including the potential for wide SGLT2i implementation in HF patients, with or without T2D, we are facing a promising time for major changes in the global management of cardiovascular disease., This paper had a non-restrictive financial support of Boehringer Ingelheim and Lilly Portugal.

Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend-55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001-2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001-2010 and 83.1% from 2011, P 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.

Background: Heart Transplant (HTx) is the ultimate chance of life for end stage Heart Failure (HF). Exercise training has consistently shown the potential to improve functional capacity in various chronic heart diseases. Still, the evidence in HTx recipients is scarcer. This study aims to systematically review the literature to evaluate the effectiveness and safety of Exercise-based Cardiac Rehabilitation (EBCR) in HTx recipients and to identify possible moderators of success. Methods: We conducted a systematic review and meta-analysis of randomized controlled trials on the effect and safety of EBCR in adult HTx recipients. The primary outcome was functional capacity, measured by Peak Oxygen Uptake (pVO2). We searched CENTRAL, MEDLINE, Embase, Scopus, and Web of Knowledge databases until December 2020, reviewed references of relevant articles and contacted experts. Usual care (UC), the different dosages of exercise regimens and alternative settings were allowed as comparators. A quantitative synthesis of evidence was performed using random-effects meta-analyses. Results: A total of 11 studies with 404 patients were included. Nine studies comprising 306 patients compared EBCR with usual care. They showed that EBCR improved pVO2 compared to usual care (Mean Difference [MD] 3.03 mL/kg/min, 95% CI [2.28-3.77]; I2 = 32%). In the subgroup analysis, including length of intervention and timing of enrollment after HTx, no significant moderator was found. Two trials, with 98 patients total, compared High Intensity Interval Training (HIIT) and Moderate Intensity Continuous Training (MICT). HIIT attained a significant edge over MICT (MD 2.23 mL/kg/min, 95% CI [1.79-2.67]; I2 = 0%). No major adverse events associated with EBCR were reported. Conclusion: We found moderate quality evidence suggesting EBCR has a significant benefit on functional capacity improvement HTx recipients at the short-term. HIIT showed superiority when compared to MICT. Research focusing long term outcomes and standardized protocols are needed to improve evidence on EBCR effectiveness.

O livro reúne seis capítulos escritos por diferentes autores: capítulo 1, Mediating Effect of the HRM on the Relationship Between the SIMS and New Product Radicality (pelos autores M. Martinez-Costa, D. Jimenez-Jimenez, Y. Castro-del-Rosario e Ledian Valle-Mestre); Capítulo 2, Reinventing Human Resource Management to Increase Organizational Efficacy (por José Rebelo dos Santos e Lurdes Pedro); capítulo 3, Employer Branding: Issues of Tailoring Your Message in the Modern Age (por Nick G. Chandler e Tamas Nemeth); capítulo 4, A Qualitative Investigation for Platform Model Conceptualization and Design: Propositions for a New Architecture (por Duygu Toplu Ya¸slıo˘glu, Murat Ya¸slıo˘glu e Aykut Berber); capítulo 5, The Utility of Human Resource Managers’ Action: A Self-centred Perception by Different Organizational Actors (por João Leite Ribeiro, Delfina Gomes e Ana Caria); e capítulo 6, About Competencies, Creativity, and Innovation in the Portuguese Textile and Clothing Sector (por Carolina Feliciana Machado e Rosa Maria Maia Miranda). Os capítulos são independentes entre si, contudo, todos abordam as diferentes facetas da inovação organizacional e dos recursos humanos no contexto moderno.

BACKGROUND: Heart failure (HF) is a growing public health problem. Sacubitril/valsartan is now recommended to be used in persistently symptomatic patients with left ventricular ejection fraction (LVEF)

© The Author(s) 2021. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/, Renin-angiotensin-aldosterone system inhibitors (RAASi) reduce morbidity and mortality in heart failure (HF) with reduced ejection fraction in a dose-dependent manner. They also have a positive impact in other cardiovascular diseases (CVDs). However, RAASi may induce hyperkalemia, a potentially life-threatening disorder. This risk is further increased in those with concomitant chronic kidney disease, diabetes mellitus, and/or in patients with hypertension. Current treatment guidelines recommend maximal RAASi dosing to improve clinical outcomes; however, this is often limited by the development of hyperkalemia. When this occurs, current guidelines recommend RAASi down-titration/interruption, which, while improving short-term prognosis, is associated with a negative long-term prognostic impact. At present, the European Society of Cardiology suggests the consideration of novel potassium binders (patiromer and sodium zirconium cyclosilicate) for the management of RAASi-associated hyperkalemia. Both drugs can reduce serum potassium levels and prevent recurrent hyperkalemia. Additionally, patiromer showed enabling of RAASi optimization in high-risk patients. Nevertheless, precise recommendations on the use of these drugs are lacking. Building upon current HF guideline recommendations, a multidisciplinary expert panel convened to design an algorithm providing practical guidance on the use of novel potassium binders/patiromer in patients with HF and/or other CVD. As a result of that effort, we present an evidence-based treatment algorithm for the management of hyperkalemia with novel potassium binders/patiromer in patients with HF and/or other CVD receiving RAASi, including the necessary monitoring to avoid induction of hypokalemia. This algorithm aims to maintain or up-titrate RAASi to optimized doses, while maintaining normokalemia, improved clinical outcomes, and long-term prognosis., This work was supported by Vifor Pharma, Portugal, via an educational grant.

Renin-angiotensin-aldosterone system (RAAS) inhibitors are a cornerstone in the treatment of heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan modulates the neurohormonal axis by inhibiting both angiotensin receptors and neprilysin, and improves neurohormonal balance more than blocking the RAAS alone.The PARADIGM-HF trial validated this new treatment option for patients with HFrEF. Sacubitril/valsartan was also more effective than enalapril in slowing disease progression by decreasing the risk of worsening heart failure requiring hospitalization or emergency admission and the need for intensified therapy, heart failure devices or cardiac transplantation. More than 70% of patients included in PARADIGM-HF were in NYHA class II, and overall, the results indicate that sacubitril/valsartan should be started in the earliest symptomatic stages of the disease.As PARADIGM-HF has excellent robustness for a cardiovascular trial, sacubitril/valsartan has been included as a new treatment option with a strong level of recommendation in the main international guidelines.This expert task force proposes a practical guide to the use of this new drug that has been endorsed by the Working Group on Heart Failure of the Portuguese Society of Cardiology. Resumo: Os inibidores do sistema renina-angiotensina-aldosterona são uma das pedras basilares no tratamento da insuficiência cardíaca com fração de ejeção reduzida. O sacubitril/valsartan promove a modulação neuro-hormonal, bloqueando os recetores da angiotensina e inibindo a neprilisina, e produz um maior equilíbrio neuro-hormonal, mais do que o bloqueio do sistema renina-angiotensina-aldosterona isoladamente. O estudo PARADIGM-HF validou essa nova opção para o tratamento de doentes com insuficiência cardíaca e fração de ejeção reduzida, em alternativa ao IECA/ARA.O sacubitril/valsartan demonstrou ser mais eficaz do que o enalapril em retardar a progressão da doença, diminuindo o risco de agravamento da insuficiência cardíaca através da diminuição da necessidade de hospitalização e da menor necessidade de intensificação terapêutica, dispositivos ou transplante cardíaco. Mais de 70% dos doentes incluídos no estudo PARADIGM-HF estavam em classe II da NYHA, suportando a utilização do sacubitril/valsartan precocemente após o início dos sintomas.Como o estudo PARADIGM-HF apresentou uma robustez sem precedentes para um estudo cardiovascular, o sacubitril/valsartan foi incluído como uma nova opção de tratamento nas Recomendações internacionais mais relevantes, com um elevado nível de evidência (I-B).Este grupo de peritos em Insuficiência Cardíaca vem propor uma orientação prática para a utilização deste novo fármaco, subscrita pelo Grupo de Estudos de Insuficiência Cardíaca da Sociedade Portuguesa de Cardiologia. Keywords: Sacubitril/valsartan, PARADIGM-HF, Practical guidance, Heart failure with reduced ejection fraction, Palavras-chave: Sacubitril/valsartan, PARADIGM-HF, Guia prático, Insuficiência cardíaca com fração de ejeção reduzida

Background. Sudden cardiac death (SCD) risk stratification in dilated cardiomyopathy (DCM) has been based on left ventricular ejection fraction (LVEF), even though SCD may occur with LVEF > 35%. Family history of unexplained SCD, especially in the young, raises concern about potential inheritable risk factors. It remains largely unknown how genetic tests can be integrated into clinical practice, particularly in the selection of implantable cardioverter defibrillator (ICD) candidates. We aimed to assess the diagnostic yield of genetic testing in DCM patients with a class I recommendation for ICD implantation, based on current guidelines. Methods. We included ambulatory stable adult patients with idiopathic or familial DCM with previously implanted ICD. Molecular analysis included 15 genes (LMNA, MYH7, MYBPC3, TNNT2, ACTC1, TPM1, CSRP3, TCAP, SGCD, PLN, MYL2, MYL3, TNNI3, TAZ, and LDB3) using next-generation sequencing. Results. We evaluated 21 patients, 12 (57%) males and 9 (43%) with familial DCM, including 3 (14%) with a family history of premature unexplained SCD. Mean age at DCM diagnosis was 40 ± 2 years, and mean age at ICD implantation was 50 ± 12 years. LVEF was 27 ± 9%, and LV end-diastolic diameter was 65 ± 7 mm. Genetic variants were found in six (29%) patients, occurring in 5 genes: TPM1, TNNT2, MYH7, PLN, and MYBPC3. The majority were classified as variants of uncertain significance. Family history of SCD was present in both patients with PLN variants. Conclusion. In patients with DCM and ICD, genetic variants could be identified in a significant proportion of patients in several genes, highlighting the potential role of genetics in DCM SCD risk stratification.

Introduction: Dilated cardiomyopathy (DCM) is a disease of the heart muscle characterized by ventricular dilatation and impaired systolic function. Familial forms account for 30-50% of cases. Autosomal dominant inheritance is the predominant pattern of transmission. Causal genetic variants have been identified in several genes and molecular diagnosis has implications for genetic counseling and risk stratification. Objective: We aimed to estimate the frequency of genetic variants and the molecular basis of DCM in Portugal. Methods: We performed a multicenter study of unrelated patients, recruited between 2013 and 2014. Variants in 15 genes were screened using PCR with direct sequencing (next-generation sequencing with at least 30-fold coverage combined with Sanger sequencing). Results: A total of 107 patients were included, 64 (60%) men, mean age at diagnosis 38±13 years, with 48 (45%) familial cases. In total, 31 rare variants in eight genes (mainly in MYBPC3, TNNT2 and LMNA) were identified, in 28 patients (26%). Only four variants had been previously described in association with DCM, 11 with hypertrophic cardiomyopathy, and nine variants were novel. Four variants were likely pathogenic and the remainder were of uncertain significance. We found no major differences in the main clinical and imaging characteristics between patients with or without rare variants and patients with likely pathogenic variants. Conclusions: Our results reflect the complexity and diversity of DCM genetics. For better interpretation of the pathogenicity of the variants found and their causative roles in DCM, molecular cascade screening of families is imperative. Further insight into genotype-phenotype correlations and risk stratification is desirable. Resumo: Introdução: A miocardiopatia dilatada (MCD) é uma doença do músculo cardíaco caracterizada por dilatação ventricular e compromisso da função sistólica. As formas familiares são responsáveis por 30 a 50% dos casos. O padrão de hereditariedade predominante é o autossómico dominante. Variantes genéticas causais foram identificadas em vários genes e o diagnóstico molecular tem implicações para o aconselhamento genético e estratificação de risco. Objetivo: Avaliar a base molecular da MCD em Portugal. Métodos: Estudo multicêntrico de doentes não relacionados, recrutados entre 2013 e 2014. Foram analisados 15 genes, através da técnica de PCR com sequenciação direta (NGS com pelo menos uma cobertura de 30 vezes combinada com sequenciação de Sanger). Resultados: Foram incluídos 107 pacientes, 64 (60%) homens, idade média ao diagnóstico de 38 ± 13 anos, com 48 (45%) casos familiares. Foram identificadas 31 variantes raras, em oito genes, (principalmente MYBPC3, TNNT2 e LMNA) em 28 pacientes (26%). Apenas quatro variantes tinham sido previamente descritas em associação com MCD, 11 com miocardiopatia hipertrófica e nove variantes eram novas. Quatro variantes foram classificadas como provavelmente patogénicas e as restantes de significado incerto. Não encontrámos diferenças significativas nas principais características clínicas e imagiológicas entre doentes com ou sem variantes raras e doentes com variantes provavelmente patogénicas. Conclusões: Estes resultados refletem a complexidade e diversidade genética da MCD. Para uma melhor interpretação da patogenicidade das variantes e potencial causalidade, o rastreio molecular das famílias é imperativo. Uma visão mais aprofundada das correlações genótipo-fenótipo e da estratificação de risco é desejável. Keywords: Dilated cardiomyopathy, Genetic variant, Next-generation sequencing, Palavras-chave: Miocardiopatia dilatada, Variante genética, Sequenciação massiva paralela

Telemedicine (TM) is potentially a way of escalating heart failure (HF) multidisciplinary integrated care. Despite the initial efforts to implement TM in HF management, we are still at an early stage of its implementation. The coronavirus disease 2019 pandemic led to an increased utilisation of TM. This tendency will probably remain after the resolution of this threat. Face-to-face medical interventions are gradually transitioning to the virtual setting by using TM. TM can improve healthcare accessibility and overcome geographic inequalities. It promotes healthcare system efficiency gains, and improves patient self-management and empowerment. In cooperation with human intervention, artificial intelligence can enhance TM by helping to deal with the complexities of multicomorbidity management in HF, and will play a relevant role towards a personalised HF patient approach. Artificial intelligence-powered/telemedical/heart team/multidisciplinary integrated care may be the next step of HF management. In this review, the authors analyse TM trends in the management of HF patients and foresee its future challenges within the scope of HF multidisciplinary integrated care.

Digital, Background: Poor health-related quality of life (HRQL) is common in heart failure (HF), but there are few data on HRQL in HF and the association between HRQL and mortality outside Western countries. Methods: We used the Kansas City Cardiomyopathy Questionnaire–12 (KCCQ-12) to record HRQL in 23 291 patients with HF from 40 countries in 8 different world regions in the G-CHF study (Global Congestive Heart Failure). We compared standardized KCCQ-12 summary scores (adjusted for age, sex, and markers of HF severity) among regions (scores range from 0 to 100, with higher score indicating better HRQL). We used multivariable Cox regression with adjustment for 15 variables to assess the association between KCCQ-12 summary scores and the composite of all-cause death, HF hospitalization, and each component over a median follow-up of 1.6 years. Results: The mean age of participants was 65 years; 61% were men; 40% had New York Heart Association class III or IV symptoms; and 46% had left ventricular ejection fraction ≥40%. Average HRQL differed between regions (lowest in Africa [mean± SE, 39.5±0.3], highest in Western Europe [62.5±0.4]). There were 4460 (19%) deaths, 3885 (17%) HF hospitalizations, and 6949 (30%) instances of either event. Lower KCCQ-12 summary score was associated with higher risk of all outcomes; the adjusted hazard ratio (HR) for each 10-unit KCCQ-12 summary score decrement was 1.18 (95% CI, 1.17–1.20) for death. Although this association was observed in all regions, it was less marked in South Asia, South America, and Africa (weakest association in South Asia: HR, 1.08 [95% CI, 1.03–1.14]; strongest association in Eastern Europe: HR, 1.31 [95% CI, 1.21–1.42]; interaction P, Ciencias Medicas y de la Salud

Background: Tele-rehabilitation (TR) may be an effective alternative or complement to centre-based cardiac rehabilitation (CBCR) with heart failure (HF) patients, helping overcome accessibility problems to CBCR. The aim of this study is to systematically review the literature in order to assess the clinical effectiveness of TR programs in the management of chronic HF patients, compared to standard of care and standard rehabilitation (CBCR). Methods and Results: We conducted a systematic review and meta-analysis of randomized controlled trials on the effect and safety of TR programs in HF patients, regarding cardiovascular death, heart failure-related hospitalizations, functional capacity and quality of life. We searched 4 electronic databases up until May 2020, reviewed references of relevant articles and contacted experts. A quantitative synthesis of evidence was performed by means of random-effects meta-analyses. We included 17 primary studies, comprising 2206 patients. Four studies reported the number of hospitalizations (TR: 301; Control: 347). TR showed to be effective in the improvement of HF patients’ functional capacity in the 6 Minute Walk-Test (Mean Difference (MD) 15.86; CI 95% [7.23; 24.49]; I2 = 74%) and in peak oxygen uptake (pVO2) results (MD 1.85; CI 95% [0.16; 3.53]; I2 = 93%). It also improved patients’ quality of life (Minnesota Living with Heart Failure Questionnaire: MD −6.62; CI 95% [−11.40; −1.84]; I2 = 99%). No major adverse events were reported during TR exercise. Conclusion: TR showed to be superior than UC without CR on functional capacity improvement in HF patients. There is still scarce evidence of TR impact on hospitalization and cv death reduction. Further research and more standardized protocols are needed to improve evidence on TR effectiveness, safety and cost-effectiveness.

© Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC-BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/), Heart failure (HF) is a major health problem with a significant impact on morbidity, mortality, quality of life and healthcare costs. Despite the positive impact of disease-modifying therapies developed over the last four decades, HF mortality and hospitalization remain high. We aim at reviewing the evidence supporting the use of sodium-glucose co-transporter-2 (SGLT-2) inhibitors, as a novel strategy for HF with reduced ejection fraction (HFrEF) treatment. The consistent observation of a reduction in HF hospitalizations in type-2 diabetes cardiovascular safety trials EMPA-REG OUTCOME, CANVAS, DECLARE-TIMI 58 and VERTIS raised the hypothesis that SGLT-2 inhibitors could have an impact in HF treatment. This hypothesis was first confirmed in 2019 with the DAPA-HF publication showing that dapagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations and cardiovascular mortality. This was reinforced by the EMPEROR-Reduced publication in 2020 showing that empagliflozin on top of optimized HFrEF therapy, reduced HF-hospitalizations. Both studies established SGLT-2 inhibitors as a fourth pillar of HFrEF prognosis-modifying therapy, in addition to the gold standard triple neurohormonal modulation/blockade.

Heart failure (HF) is a disabling diagnosis with an unfavorable prognosis, which is considered a worldwide public health problem and the first cause of death when compared with other cardiovascular diseases. Research showed that the relationship between psychological disorders and cardiovascular diseases increases the risk and worsens the prognosis of these diseases. Despite being the most present psychological symptoms in this population, anxiety and depression have received less attention in the context of HF. This study aimed to analyze the characteristics of HF patients, to relate their anxiety levels to depression, age, LVEF, cognitive performance, quality of life (QoL), and personality. For that, we assessed 89 patients diagnosed with HF. Results showed that higher levels of anxiety were associated with higher levels of depression, worse cognitive performance, perception of worse QoL, and lower emotional stability. When depression levels were controlled, anxiety continued to affect cognitive performance, emotional stability, and QoL. These results have important implications for clinical practice and for research in the field of psychology, showing the need for development of better approaches and management of these patients in outpatient care. (c) 2021, Associação Brasileira de Psicologia.

Aims The EMPERIAL (Effect of EMPagliflozin on ExeRcise ability and HF symptoms In patients with chronic heArt faiLure) trials evaluated the effects of empagliflozin on exercise ability and patient-reported outcomes in heart failure (HF) with reduced and preserved ejection fraction (EF), with and without type 2 diabetes (T2D), reporting, for the first time, the effects of sodium-glucose co-transporter-2 inhibition in HF with preserved EF (HFpEF). Methods and results HF patients with reduced EF (HFrEF) (≤40%, N = 312, EMPERIAL-Reduced) or preserved EF (>40%, N = 315, EMPERIAL-Preserved), with and without T2D, were randomized to empagliflozin 10 mg or placebo for 12 weeks. The primary endpoint was 6-minute walk test distance (6MWTD) change to Week 12. Key secondary endpoints included Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and Chronic Heart Failure Questionnaire Self-Administered Standardized format (CHQ-SAS) dyspnoea score. 6MWTD median (95% confidence interval) differences, empagliflozin vs. placebo, at Week 12 were −4.0 m (−16.0, 6.0; P = 0.42) and 4.0 m (−5.0, 13.0; P = 0.37) in EMPERIAL-Reduced and EMPERIAL-Preserved, respectively. As the primary endpoint was non-significant, all secondary endpoints were considered exploratory. Changes in KCCQ-TSS and CHQ-SAS dyspnoea score were non-significant. Improvements with empagliflozin in exploratory pre-specified analyses of KCCQ-TSS responder rates, congestion score, and diuretic use in EMPERIAL-Reduced are hypothesis generating. Empagliflozin adverse events were consistent with those previously reported. Conclusion The primary outcome for both trials was neutral. Empagliflozin was well tolerated in HF patients, with and without T2D, with a safety profile consistent with that previously reported in T2D. Hypothesis-generating improvements in exploratory analyses of secondary endpoints with empagliflozin in HFrEF were observed.

© 2020 Sociedade Portuguesa de Cardiologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/bync-nd/4.0/)., Introduction and Objectives: Renin-angiotensin-aldosterone system inhibitors (RAASi) are the cornerstone of treatment of heart failure with reduced ejection fraction (HFrEF). RAASi optimization in real-life care is challenged by hyperkalemia, a potentially fatal adverse event, which can necessitate downtitration or discontinuation of RAASi and negatively impact survival in HFrEF. The literature on this problem is sparse. We performed a systematic review of studies on HFrEF to investigate the prevalence, incidence, and risk factors of hyperkalemia, RAASi prescription rates, frequency of RAASi downtitration or discontinuation due to hyperkalemia, and the potential negative effect of the latter on prognosis. Methods: We conducted a MEDLINE (PubMed) search including observational and interventional studies published between January 1987 and May 2018. Results: A total of 30 observational and 18 interventional studies were included in the review. The incidence of hyperkalemia reported was between 0% and 63% in observational studies and was between 0% and 30% in clinical trials. Risk factors for hyperkalemia included RAASi prescription, older age, diabetes, and chronic kidney disease. In real-life studies, RAASi were downtitrated or discontinued in 3-22% of HFrEF patients; hyperkalemia was the reported cause in 5% of cases. No reports were found on the impact on prognosis of RAASi downtitration or discontinuation due to hyperkalemia. Conclusions: Hyperkalemia and RAASi downtitration or discontinuation are frequent, particularly in real-life HFrEF studies. Further research is needed to clarify the role of RAASi downtitration or discontinuation due to hyperkalemia and to assess its long-term prognostic impact in HFrEF patients., This work was supported by OM Pharma (Amadora, Portugal) for the payment of medical writing support. OM Pharma had no role in the study design, or in the collection, analysis and interpretation of data, or in the writing of the manuscript, or the decision to submit the manuscript for publication. The views expressed in the manuscript are those of the authors and not necessarily those of OM Pharma.

[Abstract] Aim. To investigate the characteristics long-term prognostic implications (up to ∼2.2 years) of atrial fibrillation (AF) compared to sinus rhythm (SR), between acute and chronic heart failure (HF) with reduced (HFrEF

Introduction and Objectives: Aortic dilatation can develop late after tetralogy of Fallot repair. Its extension beyond the aortic root is not clearly understood. We aimed to assess the prevalence and predictors of ascending aorta dilatation to set up an imaging protocol. Methods: In this prospective study including adult patients after tetralogy of Fallot repair followed at a referral center, we assessed the aorta by cardiovascular magnetic resonance and defined ascending aorta dilatation as an observed-to-expected ratio >1.5. Results: We included 78 adults (mean age 31±10 years; 56% female), with a mean follow-up of 23±7 years since tetralogy of Fallot repair. The prevalence of ascending aorta dilatation was 11.5%. The ascending aorta was larger than the sinuses of Valsalva in 12.8% of cases. Patients with ascending aorta dilatation were older, predominantly male, with later repair and larger left ventricular mass and volumes. By multivariate analysis left ventricular mass index (LVMI) was the only factor independently associated with ascending aorta dilatation (odds ratio 1.10, 95% confidence interval 1.01-1.20, p=0.03). A cut-off value of ≥57.9 g/m2 for LVMI had 89% sensitivity and 71% specificity for ascending aorta dilatation. Conclusions: Ascending aorta assessment as part of a routine cardiovascular magnetic resonance study after tetralogy of Fallot repair is recommended to screen for future aortic complications, particularly in males and older patients, and those with later repair and larger left ventricles. LVMI assessment has potential as a screening tool for ascending aorta dilatation with future clinical implications. Resumo: Introdução e objetivos: A dilatação da aorta é uma complicação tardia após correção da tetralogia de Fallot. A sua extensão além da raiz da aorta não está bem definida. Pretendemos avaliar a prevalência e os preditores de dilatação da aorta ascendente para elaborar um protocolo imagiológico. Métodos: Estudo prospetivo com adultos operados a tetralogia de Fallot seguidos num centro de referência. Estudamos a aorta por ressonância magnética cardiovascular e definimos dilatação da aorta ascendente pelo rácio observado-esperado > 1,5. Resultados: Incluímos 78 adultos (idade média 31 ± 10 anos; 56% mulheres); seguimento médio de 23 ± 7 anos desde a cirurgia. A prevalência de dilatação da aorta ascendente foi 11,5%. A aorta ascendente era maior do que os seios de Valsalva em 12,8% dos casos. Os doentes com dilatação da aorta ascendente eram mais velhos, maioritariamente homens, operados mais tarde, com massa e volumes ventriculares esquerdos maiores. Na análise multivariada a massa ventricular esquerda indexada foi a única variável independente associada a dilatação da aorta ascendente (odds ratio 1,10; intervalo de confiança de 95% 1,01-1,20; p = 0,03). A massa ventricular esquerda indexada ≥ 57,9 g/m2 apresentou uma sensibilidade de 89% e uma especificidade de 71% para dilatação da aorta ascendente. Conclusões: Recomendamos a inclusão da aorta ascendente na avaliação por ressonância magnética da tetralogia de Fallot operada, para prevenir complicações aórticas futuras, em particular em homens, doentes mais velhos, operados mais tarde e com ventrículos esquerdos maiores. A massa ventricular esquerda indexada tem potencial para ser usada no rastreio da dilatação da aorta ascendente com implicações clínicas futuras. Keywords: Aortic dilatation, Ascending aorta, Cardiovascular magnetic resonance, Tetralogy of Fallot, Palavras-chave: Dilatação da aorta, Aorta ascendente, Ressonância magnética cardiovascular, Tetralogia de Fallot

Introduction: Biomarkers in dilated cardiomyopathy (DCM) reflect various pathobiological processes, including neurohormonal activation, oxidative stress, matrix remodeling, myocyte injury and myocyte stretch. We assessed the role of biomarkers in clinical and echocardiographic parameters and in left ventricular (LV) reverse remodeling (LVRR). Methods: In this prospective study of 50 DCM patients (28 men, aged 59±10 years) with LV ejection fraction (LVEF) 10 U in LVEF after optimal medical therapy. Results: Baseline LVEF was 25.4±9.8% and LV end-diastolic diameter (LVEDD)/body surface area (BSA) was 34.2±4.5 mm/m2. LVRR occurred in 34% of patients within 17.6±15.6 months. No correlation was found between B-type natriuretic peptide (BNP), 25-hydroxyvitamin D (25(OH)D), CA-125, high-sensitivity C-reactive protein (hs-CRP), lipoprotein(a) [Lp(a)], noradrenaline, adrenaline, renin or aldosterone and LVRR. Patients in NYHA class III or IV, with pulmonary congestion or ankle edema, had higher CA-125, cystatin C, BNP and hs-CRP levels (p10 U da LVEF, após a terapêutica médica otimizada. Resultados: A LVEF basal foi de 25,4±9,8% e o diâmetro do VE (LVD)/BSA de 34,2±4,5 mm/m2. A LVRR ocorreu em 34%, em 17,6±15,6 meses. Não houve correlação entre BNP, 25-OH-vit D, CA 125, hsCRP, Lp(a), noradrenalina, adrenalina, renina, aldosterona e LVRR. Doentes em classe NYHA (III-IV), com congestão pulmonar ou edema periférico apresentaram níveis mais elevados de CA 125, cistatina C, BNP e hsCRP (p

Aims To investigate the incidence, haemodynamic alterations and 90-day mortality of acute kidney injury (AKI) in patients with cardiogenic shock. We assessed the utility of creatinine, urine output (UO) and cystatin C (CysC) definitions of AKI in prognostication. Methods and results Cardiogenic shock patients with serial plasma samples (n = 154) from the prospective multicenter CardShock study were included in the analysis. Acute kidney injury was defined and staged according to the KDIGO criteria by creatinine (AKI(crea)) and/or UO (AKI(UO)). CysC-based AKI (AKI(CysC)) was defined similarly to AKI(crea). Changes in haemodynamic parameters were assessed over time from baseline until 96 h. Mean age of the study population was 66 +/- 12 years and 74% were men. Median baseline creatinine was 1.12 [interquartile range (IQR) 0.87-1.54] mg/dL and CysC 1.19 (IQR 0.90-1.69) mg/L. The 90-day mortality was 38%. The incidences for AKI were: AKI(crea) 31%, AKI(UO) 50%, and AKI(Cysc) 33%. AKI(crea) [odds ratio (OR) 12.2, 95% confidence interval (CI) 4.1-36.0] and AKI(CysC) (OR 2.5, 95% CI 1.1-6.1), but not AKI(UO), were independent predictors of mortality. However, a stricter UO cut-off of < 0.3 mL/kg/h for 6 h was independently associated with 90-day mortality (OR 3.6, 95% CI 1.4-9.3). Development of AKI was associated with persistently elevated central venous pressure and decreased cardiac index and mean arterial pressure. Conclusions Acute kidney injury is frequent in patients with cardiogenic shock and especially AKI(crea) predicts poor outcome. The KDIGO UO criterion seems, however, rather liberal and a stricter AKI definition of UO

Resumo: A insuficiência cardíaca é uma síndrome com elevada prevalência, morbilidade e mortalidade, sendo, no entanto, pouco reconhecida junto dos cidadãos e decisores políticos. O presente documento foi elaborado por um conjunto de peritos constituído por médicos especialistas em cardiologia, medicina interna e medicina geral e familiar, e pretende expor detalhadamente o problema da insuficiência cardíaca em Portugal a vários níveis: peso da síndrome, diagnóstico, tratamento e acompanhamento dos doentes. Para tal, são identificados e discutidos em detalhe os diferentes aspetos inerentes ao manejo da síndrome durante o processo assistencial, nas várias fases da doença e que incluem doentes hospitalizados e em ambulatório. De modo a otimizar a assistência médica prestada a estes doentes, são apontadas diversas soluções e estratégias a curto, médio e longo prazo com potencial para melhorarem a articulação e utilização dos recursos disponíveis. Pretendeu‐se desta forma destacar estratégias que, não se traduzindo num modelo único de melhoria, poderão ser adaptadas às diferentes especificidades regionais, de modo a aumentar o reconhecimento e a atenção prestada à insuficiência cardíaca em Portugal. Abstract: Heart failure is a syndrome with high prevalence, morbidity and mortality, but awareness of the disease is poor among the general public and policy makers. This document, which was prepared by a group of experts consisting of cardiologists, internists and general practitioners, aims to set out in detail the problem of heart failure in Portugal at several levels: burden of the disease, diagnosis, treatment and monitoring. To this aim, different aspects of the management of the various stages of the disease are identified and discussed in detail, covering both outpatients and hospitalized patients. In order to optimize the medical care provided to these patients, various short‐, medium‐ and long‐term solutions and strategies are put forward that have the potential to improve the integration and use of available resources. The intention is to highlight strategies that are not based on a single model but can be adapted to different regional circumstances, in order to increase awareness and improve management of heart failure in Portugal. Palavras‐chave: Insuficiência cardíaca, Documento de consensos, Prevalência, Tratamento multidisciplinar integrado, Impacto socioeconómico, Keywords: Heart failure, Consensus statement, Prevalence, Integrated multidisciplinary treatment, Socioeconomic impact

Heart failure (HF) is a chronic syndrome associated with poor prognosis and high healthcare costs, mainly due to frequent hospitalizations. These are preceded by changes in several physiological parameters, creating an opportunity for early detection and treatment of hemodynamic unbalance, and hospitalizations avoidance. Invasive telemonitoring systems have proven efficacy on this detection. Conversely, non-invasive systems need further evidence, mainly due to poor technological adherence.

Sodium glucose cotransporter 2 (SGLT2) inhibitors are a class of drugs that were primarily developed for the treatment of type 2 diabetes mellitus. However, these agents have shown to provide additional beneficial effects. We will discuss three main topics regarding the use of SGLT2 inhibitors: noncardiovascular effects, cardiovascular benefits, and novel clinical indications. Multiple clinical trials and preliminary studies across varying disciplines have shown that these agents exhibit cardiorenal-protective benefits, retinoprotective benefits, and may aid in weight loss without causing marked hypoglycemia. Therefore, these agents represent an avenue in clinical practice to manage comorbid conditions in the hyperglycemic patient. Because of their multifaceted effects and robust action, SGLT2 inhibitors represent therapy options for providers that not only provide beneficial clinical results but also reduce total patient drug burden.钠-葡萄糖协同转运蛋白-2(SGLT2)抑制剂是一类主要用于治疗2型糖尿病的药物。然而, 这些制剂已经显示额外的益处。我们将讨论有关SGLT2抑制剂使用的三个主要方向:非心血管效果、心血管益处和新的临床适应症。跨学科的多项临床试验和初步研究表明, 这些药物显示出保护心肾以及视网膜的好处, 并可能有助于减肥, 而且不会导致明显的低血糖。因此, 这些药物代表了临床实践中管理高血糖患者共存疾病的一条途径。由于SGLT2抑制剂的多方面效应和强大的作用, SGLT2抑制剂提供了新的治疗选项, 不仅有好的临床结果, 而且减少了患者的总药物负担。.

Introduction: Cardiogenic shock complicating acute myocardial infarction has a very high mortality. Our present study focuses on serial measurement of lactate during admission due to cardiogenic shock and the prognostic effect of lactate and a relative change in lactate in patients after admission and the institution of intensive care treatment. Methods and Results: This is a secondary analysis of the CardShock study. Data on lactate at baseline were available on 217 of 219 patients. In the study population, the median baseline lactate was 2.8 mmol/L (min-max range, 0.5-23.1 mmol/L). At admission, lactate was predictive of 30-day mortality with an adjusted Hazard ratio (HR) of 1.20 mmol/L (95% confidence interval, CI 1.14-1.27). Within the first 24 h of admission, baseline lactate remained predictive of 30-day mortality. Lactate at 6 h had a HR of 1.14 (95% CI 1.06-1.24) and corresponding values at 12 and 24 h had a HR of 1.10 (1.04-1.17), and of HR 1.19 (95% CI 1.07-1.32), respectively. A 50% reduction in lactate within 6 h resulted in a HR of 0.82 (95% CI 0.72-0.94). Corresponding hazard ratios at 12 and 24 h, were 0.87 (95% CI 0.76-0.98) and 0.74 (95% CI 0.60-0.91), respectively. Conclusion: The main findings of the present study are that baseline lactate is a powerful predictor of 30-day mortality, lactate at 6, 12, and 24 h after admission are predictors of 30-day mortality, and a relative change in lactate is a significant predictor of survival within the first 24 h after instituting intensive care treatment adding information beyond the information from baseline values.

Background: Cardiogenic shock (CS) is the most life-threatening manifestation of acute heart failure. Its complexity and high in-hospital mortality may justify the need for invasive monitoring with a pulmonary artery catheter (PAC). Methods: Patients with CS included in the CardShock Study, an observational, prospective, multicenter, European registry, were analyzed, aiming to describe the real-world use of PAC, evaluate its impact on 30-day mortality, and the ability of different hemodynamic parameters to predict outcomes. Results: Pulmonary artery catheter was used in 82 (37.4%) of the 219 patients. Cardiogenic shock patients who managed with a PAC received more frequently treatment with inotropes and vasopressors, mechanical ventilation, renal replacement therapy, and mechanical assist devices ( P < .01). Overall 30-day mortality was 36.5%. Pulmonary artery catheter use did not affect mortality even after propensity score matching analysis (hazard ratio = 1.17 [0.59-2.32], P = .66). Cardiac index, cardiac power index (CPI), and stroke volume index (SVI) showed the highest areas under the curve for 30-day mortality (ranging from 0.752-0.803) and allowed for a significant net reclassification improvement of 0.467 (0.083-1.180), 0.700 (0.185-1.282), 0.683 (0.168-1.141), respectively, when added to the CardShock risk score. Conclusions: In our contemporary cohort of CS, over one-third of patients were managed with a PAC. Pulmonary artery catheter use was associated with a more aggressive treatment strategy. Nevertheless, PAC use was not associated with 30-day mortality. Cardiac index, CPI, and SVI were the strongest 30-day mortality predictors on top of the previously validated CardShock risk score.

Introduction and Objectives: Dilated cardiomyopathy (DCM) is a myocardial disease that can progress to a terminal stage, requiring heart transplantation. In this work we aim to contribute to knowledge of genetic variants in adult patients undergoing heart transplantation due to end-stage DCM, reporting the results obtained in our single-center tertiary hospital series using target next-generation sequencing (NGS). Methods and Results: Genetic variants were screened in 15 genes, preselected based on variants previously identified in DCM patients. Thirteen unrelated patients were included, nine (69%) male, mean age at diagnosis 33±13 years, eight (62%) with familial DCM. Nine genetic variants were identified in six (46%) patients: five in LMNA, two in LBD3, one in TNNT2 and one in TCAP. These variants were new in most patients. The majority were classified as of uncertain significance. Two patients were double and triple heterozygotes in the LBD3 and LMNA genes, respectively. Conclusion: Our results highlight the potential of NGS in the genetic characterization of DCM patients. LMNA is one of the most frequently mutated genes and should be included in all target gene assessments of end-stage DCM patients until more data are available. Resumo: Introdução e objetivos: A miocardiopatia dilatada é uma doença miocárdica que pode evoluir para um estádio terminal, requerendo transplante cardíaco. Neste trabalho, pretendemos contribuir para o conhecimento das variantes genéticas presentes em pacientes adultos submetidos a transplante cardíaco, descrevendo os resultados obtidos utilizando técnicas de sequenciação de ADN de nova geração. Métodos e resultados: Variantes genéticas foram pesquisadas em 15 genes pré-selecionados com base em variantes previamente identificadas em pacientes com miocardiopatia dilatada. Foram incluídos 13 pacientes não relacionados, nove (69%) do sexo masculino, com idade média na altura do diagnóstico de 33±13 anos, oito (62%) com doença familiar. Foram identificadas nove variantes genéticas em seis (46%) pacientes: LMNA-5, LBD3-2, TNNT2-1 e TCAP- 1. A maioria das variantes genéticas foi classificada como de significado incerto. Dois pacientes eram heterozigotos duplos e triplos nos genes LBD3 e LMNA, respetivamente. Conclusões: Os nossos resultados reforçam o potencial das novas tecnologias de sequenciação na caracterização genética de doentes com miocardiopatia dilatada. Até que mais dados estejam disponíveis, o gene LMNA é um dos mais frequentemente envolvidos e deverá ser incluído na avaliação de pacientes com miocardiopatia dilatada em fase terminal. Keywords: Dilated cardiomyopathy, Heart transplantation, Next-generation sequencing, Genetic variants, Palavras-chave: Miocardiopatia dilatada, Transplante cardíaco, Sequenciação de nova geração, Variantes genéticas

The current paradigm of medical therapy for heart failure with reduced ejection fraction (HFrEF) is triple neurohormonal blockade with an angiotensin-converting enzyme inhibitor (ACEI), a beta-blocker (BB) and a mineralocorticoid receptor antagonist (MRA). However, three-year mortality remains over 30%.Stimulation of counter-regulatory systems in addition to neurohormonal blockade constitutes a new paradigm, termed neurohormonal modulation. Sacubitril/valsartan is the first element of this new strategy.PARADIGM-HF was the largest randomized clinical trial conducted in HFrEF. It included 8442 patients and compared the efficacy and safety of sacubitril/valsartan versus enalapril. The primary endpoint was the composite of cardiovascular mortality and hospitalization due to HF, which occurred in 914 (21.8%) patients receiving sacubitril/valsartan and in 1117 (26.5%) patients receiving enalapril (HR 0.8, 95% CI 0.73-0.87, p=0.0000002; NNT 21). Sacubitril/valsartan reduced both primary endpoint components, as well as sudden cardiac death, death due to worsening HF, and death from all causes. Patients on sacubitril/valsartan reported less frequent deterioration of HF and of quality of life, and discontinued study medication less frequently because of an adverse event.PARADIGM-HF demonstrated the superiority of sacubitril/valsartan over enalapril, with a 20% greater impact on cardiovascular mortality compared to ACEIs. Accordingly, in 2016, the European (ESC) and American (ACC/AHA/HFSA) cardiology societies simultaneously issued a class I recommendation for the replacement of ACEIs by sacubitril/valsartan in patients resembling PARADIGM-HF trial participants. Resumo: O paradigma atual da terapêutica médica da insuficiência cardíaca com fração de ejeção reduzida (ICFEr) é o triplo bloqueio neuro-hormonal com inibidores da enzima conversora da angiotensina (IECA), bloqueadores beta-adrenérgicos (BB) e antagonistas dos recetores mineralocorticóides (ARM). Contudo, a mortalidade a três anos destes doentes mantém-se superior a 30%.A estimulação de sistemas contra-reguladores em adição ao bloqueio neuro-hormonal constitui um novo paradigma designado por modulação neuro-hormonal. O sacubitril/valsartan é o primeiro passo desta nova estratégia.O PARADIGM-HF foi o maior estudo aleatorizado realizado na ICFEr, tendo incluído 8442 doentes. Comparou a eficácia e segurança do sacubitril/valsartan versus enalapril. O objetivo primário foi o composto mortalidade cardiovascular/hospitalização por IC. Este ocorreu em 914 (21,8%) doentes sob sacubitril/valsartan e 1117 (26,5%) doentes sob enalapril (hazard ratio (HR) 0,8, IC95% [0,73-0,87], p=0,0000002, número de doentes necessário para prevenir um evento [NNT]=21). O sacubitril/valsartan reduziu ambos os componentes do objetivo primário. Diminuiu a morte súbita cardíaca, a devida a agravamento da IC e também a morte por todas as causas. Nos doentes sob sacubitril/valsartan ocorreu menos frequentemente agravamento da IC, deterioração da qualidade de vida e interrupção da medicação em consequência de um efeito adverso.O PARADIGM-HF demonstrou superioridade do sacubitril/valsartan relativamente ao enalapril, sendo o seu efeito sobre a mortalidade cardiovascular 20% superior ao dos IECAs. Assim, as Sociedades Europeia (ESC) e Americanas (ACC/AHA/HFSA) de Cardiologia incluíram, simultaneamente, em 2016 uma recomendação de Classe I para substituição dos IECAs pelo sacubitril/valsartan em doentes com características semelhantes aos participantes do ensaio PARADIGM-HF. Keywords: Heart failure with reduced ejection fraction, Neurohormonal modulation, Angiotensin-receptor neprilysin inhibitor, Sacubitril/valsartan, Cardiovascular mortality, Hospitalization due to heart failure, PARADIGM-HF, Palavras-chave: Insuficiência cardíaca com fração de ejeção reduzida, Modulação neuro-hormonal, Inibidor da neprilisina e dos recetores da angiotensina (INRA), Sacubitril/valsartan, Mortalidade cardiovascular, Hospitalização por insuficiência cardíaca, PARADIGM-HF