ABC | Volume 114, Nº1, January 2019

Review Article Fernandes et al. Heart Failure with Preserved Ejection Fraction Arq Bras Cardiol. 2020; 114(1):120-129 Figure 2 – Potential therapeutic targets and drugs evaluated in HFpEF.ACEI/ARB: angiotensin-converting enzyme inhibitors/angiotensin II receptor blocker;ARNI:angiotensin receptor neprilysin inhibitor; BB: Beta Blockers; MRA: mineralocorticoid receptor antagonists; PH: pulmonary hypertension. Diuretics Riociguat and Vericiguat Sildenafil Nitrates and Nitrites Digoxin Ivabradine ARNI MRA ACEI/ARB BB Ranolazine Therapeutic Targets • Diastolic dysfunction • Fibrosis and structural changes • Chronotropic incompetence • Fluid retention • PH and intracavitary pressures • Comorbidities • Physical conditioning • Functional adaptation • Symptoms Albuterol Monitoring Exercise Iron Supplementation Comorbidities Pacing Intracardiac Shunt Therapeutic Targets Original; Pathophysiology and Treatment of Heart Failure with Preserved Ejection Fraction: State of the Art and Future Perspectives 16. Pacing Patients with HFpEF and chronotropic incompetence may benefit from pacemaker devices, which may help to restore the normal HR during daily activity and exercise. The Rate-Adaptive Atrial Pacing In Diastolic Heart Failure (RAPID-HF) trial 39 aims to evaluate the impact of this intervention on short-term exercise capacity, symptoms and quality of life. 17. Iron Supplementation Iron kinetics is part of the initial evaluation of patients with HF. Intravenous iron supplementation is part of the therapeutic approach in patients with HFrEF and reduced iron stores. 3 The Effect of IV Iron Ferric Carboxymaltose (Ferinject) on Exercise Tolerance, Symptoms and Quality of Life in Patients With Heart Failure With Preserved Ejection Fraction and Iron Deficiency With and Without Anaemia, the “FAIR” trial, 40 aims to evaluate the effect of intravenous iron on exercise capacity, quality of life, NYHA functional class, mortality and hospitalizations for HF in patients with HFpEF and iron deficiency, with or without anemia. 18. Sodium-glucose cotransporter-2 inhibitors (SGLT2i) HF and diabetes frequently coexist, associated with an increased risk of cardiovascular mortality and HF hospitalization. 41 Several studies with SGLT2 inhibitors have demonstrated a significant reduction in HF hospitalizations in diabetic patients at high cardiovascular risk or with established cardiovascular disease ( Empagliflozin, Cardiovascular Outcomes, and Mortality in Type 2 Diabetes “EMPA-REG”, 42 Canagliflozin and Cardiovascular and Renal Events in Type 2 Diabetes “CANVAS”, 43 Dapagliflozin and Cardiovascular Outcomes in Type 2 Diabetes “DECLARE” 44 trials ). Given the potential benefits of this pharmacological group in improving diastolic function in patients with HF, 45 studies are underway to determine the impact of these drugs in patients with HFpEF, with and without diabetes ( A Phase III Randomised, Double-blind Trial to Evaluate the Effect of 12 Weeks Treatment of Once Daily EMPagliflozin 10 mg Compared With Placebo on ExeRcise Ability and Heart Failure Symptoms, In Patients With Chronic HeArt FaiLure With Preserved Ejection Fraction (HFpEF) “EMPERIAL – Preserved”, 46 Dapagliflozin in PRESERVED Ejection Fraction Heart Failure “PRESERVED-HF”, 47 EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction “EMPEROR-Preserved” 48 ). Conclusions HFpEF is a common pathology, still poorly understood and without any treatment proven to be effective in reducing morbidity or mortality. There seems to be no single cause to justify the failure of the obtained results; however, potential contributions can be identified: incomplete understanding of the pathophysiology, heterogeneity of the studied population, lack of universal diagnostic criteria with recruitment of patients without true HFpEF or at the very early stages, treatment not targeting the predominant pathophysiological mechanism, suboptimal designs or weak statistical power of the trials. The pathophysiology of HFpEF is multifactorial, with several mechanisms and comorbidities involved, and probably different from those of HFrEF. It results from a complex interaction of 127