ABC | Volume 112, Nº6, June 2019

Review Article Heart Failure with Mid-Range Ejection Fraction – State of the Art Evandro Tinoco Mesquita , Letícia Mara dos Santos Barbetta , Eduardo Thadeu de Oliveira Correi a Hospital Universitário Antônio Pedro, Niterói, RJ – Brazil Keywords Heart Failure/physiopathology; Stroke Volume; Natriuretics Peptides; Diagnostic Imaging; Electrocardiography; Ecocardiography; Magnetic Resonance Imaging. Mailing Address: Letícia Mara dos Santos Barbetta • Hospital Universitário Antônio Pedro - Av. Marquês do Paraná, 303. Postal Code 24033-900, Niterói, RJ – Brazil E-mail: leticiabarbetta@gmail.com Manuscript received August 20, 2018, revised manuscript December 26, 2018, accepted February 13, 2019 DOI: 10.5935/abc.20190079 Abstract In 2016, the European Society of Cardiology (ESC) recognized heart failure (HF) with ejection fraction between 40 and 49% as a new HF phenotype, HF with mid-range ejection fraction (HFmrEF), with the main purpose of encouraging studies on this new category. In 2018, the Brazilian Society of Cardiology adhered to this classification and introduced HFmrEF in Brazil. This paper presents a narrative review of what the literature has described about HFmrEF. The prevalence of patients with HFmrEF ranged from 13 to 24% of patients with HF. Analyzing the clinical characteristics, HFmrEF shows intermediate characteristics or is either similar to HF with preserved ejection fraction (HFpEF) or to HF with reduced fraction (HFrEF). Regarding the prognosis, HFmrEF’s all-cause mortality is similar to HFpEF’s and lower than HFrEF’s. Studies that analyzed cardiac mortality concluded that there was no significant difference between HFmrEF and HFrEF, both of which were lower than HFpEF. Despite the significant increase of publications onHFmrEF, there is a great scarcity of prospective studies and clinical trials that allow delineating specific therapies for this new phenotype. To better treat HFmrEF patients, it is fundamental that cardiologists and internists understand the differences and similarities of this new phenotype. Introduction The classification and characterization of heart failure (HF) by phenotypes has an important relevance in clinical practice, since these phenotypes are currently based on left ventricular ejection fraction (LVEF) and have different characteristics in relation to prognosis and treatment.¹ Classically, two main HF phenotypes have been described; the HF with reduced ejection fraction (HFrEF) with LVEF < 40% and the HF with preserved ejection fraction (HFpEF), with LVEF ≥ 50%. 2-4 Different guidelines have proposed a new phenotype in the current decade, the HF with mid-range ejection fraction (HFmrEF). The American College of Cardiology/American Heart Association published a new HF guideline in 2013, in which patients with LVEF between 41% and 50% were classified as “borderline” HFpEF.² In 2016, the ESC recognized HF with LVEF between 40% and 49% as a distinct phenotype; the HFmrEF, mainly intended to stimulate studies that address epidemiology, etiology, characteristics, and prognostics of this new category.³ Finally, the Brazilian Society of Cardiology (BSC) introduced HFmrEF as a new clinical phenotype in its 2018 guideline of acute and chronic HF. 5 With the introduction of this new classification, HFmrEF has received great attention and, consequently, has been better studied and characterized. The present review study aims to describe what is currently known about HFmrEF and discuss future perspectives that will contribute to a better approach for this group of patients. Epidemiology Prevalence In the United States, it is estimated that more than 6.5 million people have HF, 6 and the percentage of individuals with HFmrEF is between 13% and 24%. 7,8 The prevalence of HFmrEF in studies performed with hospitalized patients ranged from 13% to 26%, 7,9-12 while the prevalence of HFmrEF in outpatients varied from 9% to 21%. 8,13-17 The last census of Brazilian Institute for Geography and Statistics (IBGE) in 2010 census showed an increase in the elderly population in Brazil, and therefore a great potential for the increase of at-risk HF patients. In the DIGITALIS study performed in the city of Niterói, state of Rio de Janeiro, Brazil, a prevalence of 9.3% of HF was identified in patients from the family physician program (59 individuals among 633 volunteers), 18 in which 64.2% of these patients were characterized as having HFpEF and 35% as HFrEF. 18 Recently, according to unpublished data based on the DIGITALIS study database, the prevalence of HFmrEF patients in Niterói was 22%, HFrEF was 19% and HFpEF was 59%. Diagnosis According to the latest acute HF guideline of BSC, 5 the diagnosis of HF is based on the combination on medical history findings, physical examination, electrocardiogram and chest x-ray results, as detailed in figure 1. An echocardiogram should be performed for diagnostic confirmation if there is clinical suspicion of HF. In low suspicion cases or if there are diagnostic doubts, the measurement of brain natriuretic peptides (BNP and/or NT-proBNP) and an echocardiogram should be performed, if available. A normal echocardiogram and/or plasma BNP levels<35 pg/mL and/or NT-proBNP<125 pg/mL make the HF diagnosis improbable. In the presence of BNP levels > 35 pg/mL and/or NT-proBNP > 125 pg/mL and/or altered echocardiogram results, the HF diagnosis becomes probable. The LVEF echocardiography evaluation contributes 784