IJCS | Volume 31, Nº6, November / December 2018

653 Mesquita et al. HFPEF phenotypes Int J Cardiovasc Sci. 2018;31(6)652-661 Review Article medicine, a new paradigm that has been successfully used in oncology. This approach considers genetic variability, environment, and lifestyle of each patient, allowing an individualized approach for the treatment and prevention of diseases. 11-13 The aimof the present studywas to present a narrative reviewof the literature to describe the clinical phenotypes of HFPEF and its potential impact on the management of patients and on clinical research. Methods Bibliographic review We conducted a narrative review, from a clinical perspective, of studies published inMEDLINE using the PubMed search engine. The following MeSH (Medical Subject Heading) terms were used - (heart failure with preserved ejection fraction [tiab] OR diastolic heart failure [tiab] OR hfnef [tiab] OR hfpef [tiab]) AND (phenoc* [tiab] OR phenotype* [tiab]). The search was carried out in February 2017, and 136 articles published in the period from 1990 and 2017 were identified. Thirty articles were independently selected by four investigators for detailed analysis. Additional articles were selected from the reference lists of the retrieved articles. Pathophysiology of HFPEF Heart failure (HF) is a complex clinical syndrome characterized by symptoms and signs caused by abnormal cardiac function and/or structure that leads to decreased cardiac output and/or increased intracardiac pressures. HF patients can have different phenotypes according to morphofunctional characteristics of the disease, and receive different therapeutic approaches. 14,15 Based on this, patients are usually classified into patients with HF with reduced ejection fraction (HFrEF), marked by left ventricular ejection fraction (LVEF) lower than 40% - and HF with preserved ejection fraction (HFpEF), characterized by LVEF greater than 50%. Recently, the European Society of Cardiology has proposed a new phenotype – “HF withmidrange ejection fraction” – with intermediate ejection fraction (LVEF between 40 and 49%) and a clinical profile different fromHFeEF and HFpEF. 16 The main diagnostic criteria of HFPEF – the focus of this study – are the clinical profile of LVEF equal to or greater than 50%, increased levels of brain natriuretic peptide (BNP) (greater than 35pg/mL or NT-proBNP greater than 125 pg/mL) and at least one of these two criteria – important structural cardiac disease (left ventricular hypertrophy and/or increased left atrium) and diastolic dysfunction. 16 HFPEF is characterized by reduced end-diastolic volume, left ventricular hypertrophy, and increased left atrial volume and left ventricular filling pressure. These pathophysiological abnormalities are associated with increased left ventricular stiffness, decreased left ventricular relaxation, cardiomyocyte hypertrophy, myocardial interstitial fibrosis and reduced intramyocardial capillaries. 17-19 In addition, a proportion of patients with HFpEF present atrial fibrillation, which further aggravates cardiac function. 20 Theclassical presentations -HFeEFandHFpEF–usedto be distinguishedonly by the remodelingpattern of cardiac chambers and extension of myocardial dysfunction, culminating in different therapeutic responses. However, it is known today that morphofunctional changes are also based on molecular alterations, which are also different between these conditions. 10 Left ventricular diastolic dysfunction, an important diagnostic criterion for HFPEF, may be explained by increasedmyocardial stiffness, resulting from changes in extracellular matrix and/or cardiomyocytes. 10 There are evidence that extracellular matrix stiffness results mainly from collagen metabolism. Excess deposition of type I collagen, the subtype with the highest stiffness property, is explained by increased synthesis and/or decreased degradation of this compound. Type I collagen synthesis can be measured by procollagen type I carboxy-terminal propeptide, which derives from type I procollagen and acts as a biomarker. Decreased degradation of type I collagen is caused by downregulation of matrix metalloproteinases (MMPs) and/or upregulation of tissue inhibitors of metalloproteinases (TIMPs). TIMP-1 plasma levels have also been suggested as promising biomarkers in HFPEF. 9,10 Excess collagen is found in only one third of patients withHFPEF, even in the presence of ventricular stiffness, which usually results from an intrinsic cardiomyocyte condition, and may be related to the protein structure and/or to the disruption of the sarcomere structure. 9,10 Cardiomyocyte structuredependsdirectlyon regulation of constituent proteins, and myocardial stiffness may indicate an unbalance in this process. One of the main proteins involved in this regulation is titin, an elastic constituent protein of cardiomyocytes, with two isoforms