Iron Deficiency in Heart Failure with Reduced Ejection Fraction: Pathophysiology, Diagnosis and Treatment. / Deficiência de Ferro na Insuficiência Cardíaca com Fração de Ejeção Reduzida: Fisiopatologia, Diagnóstico e Tratamento.

Iron deficiency (ID) is an important comorbidity in heart failure with reduced ejection (HFrEF) and is highly prevalent in both anemic and non-anemic patients. In HFrEF, iron deficiency should be investigated by measurements of transferrin saturation and ferritin. There are two types of ID: absolute deficiency, with depletion of iron stores; and functional ID, where iron supply is not sufficient despite normal stores. ID is associated with worse functional class and higher risk of death in patients with HFrEF, and scientific evidence has indicated improvement of symptoms and quality of life of these patients with treatment with parenteral iron in the form of ferric carboxymaltose. Iron plays vital roles such as oxygen transportation (hemoglobin) and storage (myoblogin), and is crucial for adequate functioning of mitochondria, which are composed of iron-based proteins and the place of energy generation by oxidative metabolism at the electron transport chain. An insufficient generation and abnormal uptake of iron by skeletal and cardiac muscle cells contribute to the pathophysiology of HF. The present review aims to increase the knowledge of the pathophysiology of ID in HFrEF, and to address available tools for its diagnosis and current scientific evidence on iron replacement therapy.

A deficiência de ferro (DF) ou ferropenia é uma importante comorbidade na insuficiência cardíaca com fração de ejeção reduzida (ICFER) estável, e muito prevalente tanto nos anêmicos como não anêmicos. A ferropenia na ICFER deve ser pesquisada por meio da coleta de saturação de transferrina e ferritina. Há dois tipos de ferropenia na IC: absoluta, em que as reservas de ferro estão depletadas; e funcional, onde o suprimento de ferro é inadequado apesar das reservas normais. A ferropenia está associada com pior classe funcional e maior risco de morte em pacientes com ICFER, e evidências científicas apontam melhora de sintomas e de qualidade de vida desses pacientes com tratamento com ferro parenteral na forma de carboximaltose férrica. O ferro exerce funções imprescindíveis como o transporte (hemoglobina) e armazenamento (mioglobina) de oxigênio, além de ser fundamental para o funcionamento das mitocôndrias, constituídas de proteínas à base de ferro, e local de geração de energia na cadeia respiratória pelo metabolismo oxidativo. A geração insuficiente e utilização anormal de ferro nas células musculares esquelética e cardíaca contribuem para a fisiopatologia da IC. A presente revisão tem o objetivo de aprofundar o conhecimento a respeito da fisiopatologia da ferropenia na ICFER, abordar as ferramentas disponíveis para o diagnóstico e discutir sobre a evidência científica existente de reposição de ferro.

Deficiência de Ferro na Insuficiência Cardíaca com Fração de Ejeção Reduzida: Fisiopatologia, Diagnóstico e Tratamento / Iron Deficiency in Heart Failure with Reduced Ejection Fraction: Pathophysiology, Diagnosis and Treatment

Resumo A deficiência de ferro (DF) ou ferropenia é uma importante comorbidade na insuficiência cardíaca com fração de ejeção reduzida (ICFER) estável, e muito prevalente tanto nos anêmicos como não anêmicos. A ferropenia na ICFER deve ser pesquisada por meio da coleta de saturação de transferrina e ferritina. Há dois tipos de ferropenia na IC: absoluta, em que as reservas de ferro estão depletadas; e funcional, onde o suprimento de ferro é inadequado apesar das reservas normais. A ferropenia está associada com pior classe funcional e maior risco de morte em pacientes com ICFER, e evidências científicas apontam melhora de sintomas e de qualidade de vida desses pacientes com tratamento com ferro parenteral na forma de carboximaltose férrica. O ferro exerce funções imprescindíveis como o transporte (hemoglobina) e armazenamento (mioglobina) de oxigênio, além de ser fundamental para o funcionamento das mitocôndrias, constituídas de proteínas à base de ferro, e local de geração de energia na cadeia respiratória pelo metabolismo oxidativo. A geração insuficiente e utilização anormal de ferro nas células musculares esquelética e cardíaca contribuem para a fisiopatologia da IC. A presente revisão tem o objetivo de aprofundar o conhecimento a respeito da fisiopatologia da ferropenia na ICFER, abordar as ferramentas disponíveis para o diagnóstico e discutir sobre a evidência científica existente de reposição de ferro.

Abstract Iron deficiency (ID) is an important comorbidity in heart failure with reduced ejection (HFrEF) and is highly prevalent in both anemic and non-anemic patients. In HFrEF, iron deficiency should be investigated by measurements of transferrin saturation and ferritin. There are two types of ID: absolute deficiency, with depletion of iron stores; and functional ID, where iron supply is not sufficient despite normal stores. ID is associated with worse functional class and higher risk of death in patients with HFrEF, and scientific evidence has indicated improvement of symptoms and quality of life of these patients with treatment with parenteral iron in the form of ferric carboxymaltose. Iron plays vital roles such as oxygen transportation (hemoglobin) and storage (myoblogin), and is crucial for adequate functioning of mitochondria, which are composed of iron-based proteins and the place of energy generation by oxidative metabolism at the electron transport chain. An insufficient generation and abnormal uptake of iron by skeletal and cardiac muscle cells contribute to the pathophysiology of HF. The present review aims to increase the knowledge of the pathophysiology of ID in HFrEF, and to address available tools for its diagnosis and current scientific evidence on iron replacement therapy.

Acute necrotizing eosinophilic myocarditis possibly triggered by an antimigraine drug as an uncommon cause of acute heart failure: a case report.

BACKGROUND: Epigastric or chest pain with an abnormal electrocardiogram (ECG) in a young, otherwise healthy patient should trigger an investigation to rule out myocarditis. The myocarditis covers a wide spectrum of severity. The search for the aetiologic factor could be definitive for the success of therapy. CASE SUMMARY: A previously healthy 29-year-old woman presented to the Emergency Room with epigastric pain, eosinophilia, and an abnormal ECG. A thorough evaluation including cardiac magnetic resonance and endomyocardial biopsy was undertaken. A diagnosis of acute necrotizing eosinophilic myocarditis was made. DISCUSSION: The case is particularly unique for its suspected predisposing trigger: an antimigraine drug. A possible systemic hypersensitivity reaction, reflected by the occurrence of concomitant severe serum eosinophilia, acute myocarditis, and central nervous system vasculitis, was successfully treated with steroids, further supporting the diagnosis.

Natriuretic Peptide and Clinical Evaluation in the Diagnosis of Heart Failure Hemodynamic Profile: Comparison with Tissue Doppler Echocardiography / Peptídeo Natriurético e Avaliação Clínica no Diagnóstico do Perfil Hemodinâmico da Insuficiência Cardíaca: Comparação com Ecodopplercardiograma Tecidual

Abstract Background: Physical examination and B-type natriuretic peptide (BNP) have been used to estimate hemodynamics and tailor therapy of acute decompensated heart failure (ADHF) patients. However, correlation between these parameters and left ventricular filling pressures is controversial. Objective: This study was designed to evaluate the diagnostic accuracy of physical examination, chest radiography (CR) and BNP in estimating left atrial pressure (LAP) as assessed by tissue Doppler echocardiogram. Methods: Patients admitted with ADHF were prospectively assessed. Diagnostic characteristics of physical signs of heart failure, CR and BNP in predicting elevation (> 15 mm Hg) of LAP, alone or combined, were calculated. Spearman test was used to analyze the correlation between non-normal distribution variables. The level of significance was 5%. Results: Forty-three patients were included, with mean age of 69.9 ± 11.1years, left ventricular ejection fraction of 25 ± 8.0%, and BNP of 1057 ± 1024.21 pg/mL. Individually, all clinical, CR or BNP parameters had a poor performance in predicting LAP ≥ 15 mm Hg. A clinical score of congestion had the poorest performance [area under the receiver operating characteristic curve (AUC) 0.53], followed by clinical score + CR (AUC 0.60), clinical score + CR + BNP > 400 pg/mL (AUC 0.62), and clinical score + CR + BNP > 1000 pg/mL (AUC 0.66). Conclusion: Physical examination, CR and BNP had a poor performance in predicting a LAP ≥ 15 mm Hg. Using these parameters alone or in combination may lead to inaccurate estimation of hemodynamics.

Resumo Fundamento: Exame físico e peptídeo natriurético do tipo B (BNP) foram usados para estimar a hemodinâmica e adequar a terapia de pacientes com insuficiência cardíaca aguda descompensada (ICAD). Entretanto, correlação entre esses parâmetros e a pressão de enchimento do ventrículo esquerdo é controversa. Objetivo: Avaliar a acurácia diagnóstica do exame físico, da radiografia de tórax (RT) e do BNP para estimar a pressão atrial esquerda (PAE) avaliada pelo ecodopplercardiograma tecidual. Métodos: Pacientes admitidos com ICAD foram avaliados prospectivamente. As características diagnósticas dos sinais físicos de insuficiência cardíaca, RT e BNP para predizer elevação da PAE (> 15 mmHg), isolados ou combinados, foram calculadas. Teste de Spearman foi usado para analisar a correlação entre variáveis de distribuição não normal. O nível de significância foi 5%. Resultados: Este estudo incluiu 43 pacientes com idade média de 69,9 ± 11,1 anos, fração de ejeção ventricular esquerda de 25 ± 8.0%, e BNP de 1057 ± 1024,21 pg/mL. Individualmente, todos os parâmetros clínicos, RT e BNP apresentaram fraco desempenho para predizer PAE ≥ 15 mmHg. O escore clínico de congestão teve o pior desempenho [área sob a curva receiver operating characteristic (AUC) 0,53], seguindo-se escore clínico + RT (AUC 0,60), escore clínico + RT + BNP > 400 pg/mL (AUC 0,62) e escore clínico + RT + BNP > 1000 pg/mL (AUC 0,66). Conclusão: Exame físico, RT e BNP tiveram desempenho fraco para predizer PAE ≥15 mmHg. O uso desses parâmetros isoladamente ou em combinação pode levar a estimativa imprecisa do perfil hemodinâmico. (Arq Bras Cardiol. 2018; 110(3):270-277)

Effect of fluid and dietary sodium restriction in the management of patients with heart failure and preserved ejection fraction: study protocol for a randomized controlled trial.

BACKGROUND: Although half of all patients with heart failure (HF) have a normal or near-normal ejection fraction and their prognosis differs little from that of patients with a reduced ejection fraction, the pathophysiology of HF with preserved ejection fraction (HF-PEF) is still poorly understood, and its management poorly supported by clinical trials. Sodium and fluid restriction is the most common self-care measure prescribed to HF patients for management of congestive episodes. However, its role in the treatment of HF-PEF remains unclear. This trial seeks to compare the effects of a sodium- and fluid-restricted diet versus an unrestricted diet on weight loss, neurohormonal activation, and clinical stability in patients admitted for decompensated HF-PEF. METHODS/DESIGN: This is a randomized, parallel trial with blinded outcome assessment. The sample will include adult patients (aged ≥18 years) with a diagnosis of HF-PEF admitted for HF decompensation. The patients will be randomized to receive a diet with sodium and fluid intake restricted to 0.8 g/day and 800 mL/day respectively (intervention group) or an unrestricted diet, with 4 g/day sodium and unlimited fluid intake (control group), and followed for 7 days or until hospital discharge. The primary outcome shall consist of weight loss at 7 days or discharge. The secondary outcome includes assessment of clinical stability, neurohormonal activation, daily perception of thirst and readmission rate at 30 days. DISCUSSION: Assessment of the effects of sodium and fluid restriction on neurohormonal activation and clinical course of HF-PEF can promote a deeper understanding of the pathophysiology and progression of this complex syndrome. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov identifier: NCT01896908 (date of registration: 8 August 2013).

IRON-HF study: a randomized trial to assess the effects of iron in heart failure patients with anemia.

BACKGROUND: Anemia in heart failure patients and has been associated with increased morbi-mortality. Previous studies have treated anemia in heart failure patients with either erythropoietin alone or combination of erythropoietin and intravenous (i.v.) iron. However, the effect of i.v. or oral (p.o.) iron supplementation alone in heart failure patients with anemia was virtually unknown. AIM: To compare, in a double-blind design, the effects of i.v. iron versus p.o. iron in anemic heart failure patients. METHODS: IRON-HF study was a multicenter, investigator initiated, randomized, double-blind, placebo controlled trial that enrolled anemic heart failure patients with preserved renal function, low transferrin saturation (TSat) and low-to-moderately elevated ferritin levels. Interventions were Iron Sucrose i.v. 200 mg, once a week, for 5 weeks, ferrous sulfate 200 mg p.o. TID, for 8 weeks, or placebo. Primary endpoint was variation of peak oxygen consumption (peak VO2) assessed by ergospirometry over 3 month follow-up. RESULTS: Eighteen patients had full follow-up data. There was an increment of 3.5 ml/kg/min in peak VO2 in the i.v. iron group. There was no increment in peak VO2 in the p.o. iron group. Patients' ferritin and TSat increased significantly in both treated groups. Hemoglobin increased similarly in all groups. CONCLUSION: I.v. iron seems to be superior in improving functional capacity of heart failure patients. However, correction of anemia seems to be at least similar between p.o. iron and i.v. iron supplementation.

Anemia in heart failure: association of hepcidin levels to iron deficiency in stable outpatients.

BACKGROUND: Anemia is a prevalent condition in heart failure with multiple potential causes. The complex interaction between iron stores, hepcidin, inflammation and anemia is poorly comprehended. We tested the hypothesis that, in stable heart failure patients with anemia, hepcidin is associated with iron deficiency status irrespective of inflammation. METHODS AND RESULTS: Stable systolic heart failure outpatients with and without anemia underwent a complete iron panel, erythropoietin, hepcidin and tumor necrosis factor (TNF)-α assessment. Sixty outpatients were studied. Anemic patients (n = 38, mean hemoglobin 11.4 ± 1 g/dl) were older (69.6 ± 9.6 vs. 58 ± 10.8 years old, p < 0.01) compared with nonanemic patients (n = 22, mean hemoglobin 13.8 ± 1.1 g/dl). Iron deficiency was present in 42% of patients with anemia. TNF-α and hepcidin were 29 and 21% higher in patients with anemia, respectively, compared to nonanemic patients; however, no correlations were found between hepcidin and TNF-α levels. Hepcidin levels in the lower tertile (<31.7 ng/ml) were strongly associated with iron deficiency (OR 16.5, 95% CI 2.2-121.2; p < 0.01). CONCLUSION: In stable heart failure patients with anemia, hepcidin levels may be more importantly regulated by patients' iron stores than by inflammation.

Preditores clínicos de fração de ejeção preservada em insuficiência cardíaca descompensada / Clinical predictors of preserved left ventricular ejection fraction in decompensated heart failure

FUNDAMENTO: Identificação e impacto clínico da fração de ejeção preservada em desfechos intra-hospitalares em pacientes com insuficiência cardíaca (IC) descompensada permanecem pouco conhecidos. OBJETIVO: Descrever preditores clínicos e desfechos intra-hospitalares de pacientes com IC descompensada e fração de ejeção de ventrículo esquerdo (FEVE) preservada, e desenvolver um escore preditivo baseado em dados clínicos obtidos no momento da admissão. MÉTODOS: Internações consecutivas devido a IC descompensada (n=721) em um hospital terciário foram acompanhadas até a alta ou óbito. Mais de 80 variáveis clínicas foram avaliadas para identificar os preditores da FEVE preservada no momento da admissão. RESULTADOS: Identificou-se FEVE preservada (>50 por cento) em 224 (31 por cento) internações. Os preditores clínicos de FEVE preservada foram: idade >70 anos (p= 0,04); sexo feminino (p<0,001); etiologia não-isquêmica (p<0,001); fibrilação ou flutter atrial (p=0,001); anemia (p=0,001); pressão de pulso >45 mmHg (p<0,001); e ausência de anormalidades de condução intraventricular verificadas no eletrocardiograma (p<0,001). Um escore clínico baseado nessas variáveis foi capaz de predizer com acurácia a presença de FEVE preservada no momento da admissão hospitalar (área sob a curva ROC de 0,76). Nenhuma diferença significativa foi observada na taxa de mortalidade intra-hospitalar ou de complicações clínicas de acordo com os quintis de FEVE. CONCLUSÃO: A FEVE preservada é uma condição prevalente e mórbida entre pacientes hospitalizados por IC. Dados clínicos simples obtidos no momento da internação podem ser utilizados para predizer FEVE preservada.

BACKGROUND: Identification and clinical impact of preserved left ventricular ejection fraction (LVEF) on in-hospital outcomes in patients with acute decompensated heart failure (HF) remain poorly defined. OBJECTIVE: To describe clinical predictors and in-hospital outcomes of acute decompensated HF patients and preserved LVEF, and to develop a clinically-based predictive rule based on data acquired on admission. METHODS: Consecutive admissions for HF (n=721) at a tertiary care hospital were followed up to discharge or death. More than 80 clinical variables were evaluated to identify predictors of preserved LVEF upon admission. RESULTS: Preserved LVEF (>50 percent) was identified in 224 (31 percent) hospitalizations. Clinical predictors of preserved LVEF were age > 70 years old (p=0.04), female gender (p<0.001), non-ischemic etiology (p<0.001), atrial fibrillation or flutter (p=0.001), anemia (p=0.001), pulse pressure > 45 mmHg (p<0.01) and absence of EKG conduction abnormalities (p<0.001). A clinical score based on these variables was accurate to predict preserved LVEF upon hospital admission (area under ROC curve of 0.76). No significant differences were observed on in-hospital mortality or clinical complications according to quintiles of LVEF. CONCLUSION: Preserved LVEF is a prevalent and morbid condition among hospitalized HF patients. Simple clinical data obtained on admission might be useful for predicting preserved LVEF.