ABC | Volume 114, Nº1, January 2019

Review Article Pathophysiology and Treatment of Heart Failure with Preserved Ejection Fraction: State of the Art and Prospects for the Future Sara Lopes Fernandes, 1 Rita Ribeiro Carvalho, 1 Luís Graça Santos, 1 F ernando Montenegro Sá, 1 Catarina Ruivo, 1 Sofia Lázaro Mendes, 1 Hélia Martins, 1 João Araujo Morais 1 Centro Hospitalar de Leiria, 1 Leiria – Portugal Keywords Heart Failure/physiopathology; Heart Failure/diagnosis; Heart Failure/drug therapy; Systolic Volume; Heart Failure/ complications. Mailing Address: Sara Lopes Fernandes • Centro Hospitalar de Leiria - Rua das Olhalvas - Pousos, 2410-197, Leiria – Portugal E-mail: sarafernandes24892@gmail.com Manuscript received February 23, 2019, revised manuscript May 07, 2019, accepted May 15, 2019 DOI: https://doi.org/10.36660/abc.20190111 Introduction Heart failure (HF) is extremely prevalent and has a considerable impact on mortality and quality of life. 1 It affects nearly 1-3% of the adult population in developed countries, exponentially increasing with age and affecting more than 10% of the population over 70 years. Given the increase in the average life expectancy, better diagnosticmethods and increased comorbidities, a greater prevalence of heart failure is expected. 2 It is a clinical syndrome characterized by classic symptoms (such as fatigue, dyspnea) that may be accompanied by clinical signs (elevated jugular pressure, pulmonary crackles and peripheral edema). It is caused by structural and/or functional cardiac abnormalities, resulting in reduced cardiac output and/or elevated intracardiac pressures at rest or during stress. 3 The main terminology used to describe HF is based on the measurement of the left ventricular ejection fraction (EF), differentiating patients with reduced <40% (HFrEF), mid-range 40-49% (HFmrEF) and preserved ≥50% (HFpEF) ejection fraction. This classification is important due to different underlying etiologies, pathophysiology, available treatment and its respective response. 3 HFpEF accounts for about half of the cases of HF in developed countries. 4 Its pathophysiology is complex, heterogeneous and still poorly understood. The wide variety of phenotypes resulting from the several pathophysiological mechanisms, comorbidities and dominant clinical characteristics, make diagnosis and treatment extremely challenging. 4 Unlike HFrEF, no treatment has unquestionably shown a reduction of morbidity or mortality in patients with HFpEF or HFmrEF. Several clinical trials evaluating drugs proven to be effective in HFrEF have failed to demonstrate prognostic benefits in these patients. 4 Current recommendations are based on symptom relief, screening, and treatment of comorbidities. 3 New therapies are presently under research, especially directed at the pathophysiological mechanisms of the disease. 5 This review addresses the pathophysiology of HFpEF and summarizes the studies that have been carried out regarding treatment, including failures, hopes and future prospects. For this article, we carried out a systematic search in three databases: Medline - Pubmed, ISI Web of knowledge and Scopus, using the following keywords in English and Portuguese: "Heart failure AND preserved ejection fraction", "Heart failure AND preserved ejection fraction AND physiopathology” and “Heart failure AND preserved ejection fraction AND treatment". The study was conducted between January and March of 2019. Prospective and retrospective studies were included. Clinical cases, abstracts presented at conferences (not published as articles) and studies with a sample size of less than 10 patients were excluded. The eligibility of each study was independently assessed by three researchers. The divergent opinions regarding the relevance of the articles were resolved by consensus among the authors. Pathophysiology The pathophysiology of the disease is complex and remains insufficiently understood. It is known that these patients are generally older, females and have multiple cardiovascular comorbidities, such as hypertension, atrial fibrillation (AF), coronary artery disease (CAD), pulmonary hypertension (PH), and non-cardiovascular diseases such as diabetes, chronic kidney disease (CKD), anemia, chronic obstructive pulmonary disease (COPD), among others. They also have a higher percentage of non-cardiovascular pathologies, with a great impact on morbidity and mortality, and a lower incidence of acute myocardial infarction (AMI) as well as sudden cardiac death or death from HF. 6 Historically, HFpEF was exclusively associated with diastolic dysfunction, opposed to HFrEF, which was associated with systolic dysfunction. It is currently known that this is not such a clear-cut matter, as both types of HF may also show systolic and/or diastolic dysfunction. Different mechanisms are involved in HFpEF. This is thought to result from a complex variety of cardiac, vascular and systemic dysfunctions, with the contribution of several comorbidities. 4 (Figure 1) Diastolic dysfunction is usually present and results from structural changes (cardiac fibrosis, hypertrophy and remodeling ), microvascular dysfunction and metabolic abnormalities, with increased stiffness and decreased cardiac compliance. This leads not only to an increase in LV filling pressures, but also to structural and functional changes at the atrial, pulmonary and right ventricular levels, due to a rise in upstream pressures. The systolic reserve is also affected, mainly due to changes in the ventricular-vascular coupling ratio. 4 Atrial changes, with dilatation and remodeling, favor the appearance of AF. Pulmonary hypertension, present in 53-83% 120