While guidelines for management of heart failure with reduced ejection fraction (HFrEF) are consensual and have led to improved survival, treatment options for heart failure with preserved ejection fraction (HFpEF) remain limited and aim primarily for symptom relief and improvement of quality of life. Due to the shortage of therapeutic options, several drugs have been investigated in multiple clinical trials. The majority of these trials have reported disappointing results and have suggested that HFpEF might not be as simply described by ejection fraction as previously though. In fact, HFpEF is a complex clinical syndrome with various comorbidities and overlapping distinct phenotypes that could benefit from personalized therapeutic approaches. This review summarizes the results from the most recent phase III clinical trials for HFpEF and the most promising drugs arising from phase II trials as well as the various challenges that are currently holding back the development of new pharmacotherapeutic options for these patients.

Introduction Although initially believed to be less severe than heart failure with reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF) prevalence has increased and accounts for as much as 50% of heart failure cases [1,2]. Treatment options remain limited and aim primarily for symptom relief and improvement of quality of life [2]. Urocortin-2 (Ucn-2) belongs to the corticotrophin-releasing hormone (CRH) family and has been found to have significant beneficial hemodynamic, hormonal and renoprotective effects both in both animal models and humans with HFrEF [3,4]. Objectives In this work we studied the role of the Ucn-2/CRHR2 system in the pathophysiology of HFpEF and evaluated the efficacy of Ucn-2 as a novel therapeutic strategy in this clinical syndrome. Methods 18-week-old male ZSF1-Lean (n=26) and ZSF1-Obese (n=28) rats randomly received either Ucn-2 (15 μg/kg/day, subcutaneously) or vehicle (0.9% NaCl), for 12 weeks, resulting in 4 experimental groups: ZSF1-Lean + Ucn-2; ZSF1-Lean + vehicle; ZSF1-Obese + Ucn-2; ZSF1-Obese + vehicle. During the treatment period, evolution of cardiac (dys)function was assessed by echocardiography and exercise tolerance test. After treatment, invasive hemodynamic analysis was performed, with subsequent sample collection. Histological analysis of the left ventricle (LV) was performed as well as quantitative western blotting and RT-PCR analysis for relevant molecular markers (Figure 1). Results mRNA expression of Ucn-2 and CRHR2, as well as protein levels of CRHR2, were decreased in the LV of ZSF1-Obese rats compared to ZSF1-Lean and correlated with LV structure and diastolic function. ZSF1-Obese rats showed systemic hypertension, decreased endurance capacity and impaired LV relaxation, with preserved ejection fraction and cardiac index. Chronic Ucn-2 treatment attenuated hypertension and modestly enhanced effort tolerance. In both morphometric and echocardiographic analysis we found that ZSF1-Obese rats presented significantly higher cardiac and LV weight, compared to Lean counterparts. Cardiomyocyte cross-sectional area and fibrosis were found to be increased in Obese rats, corroborating morphometric and echocardiographic measurements. Chronic Ucn-2 treatment attenuated both cardiac hypertrophy and fibrosis. Furthermore, ZSF1-Obese rats displayed increased BNP and TNF-α LV mRNA expression, both of which were decreased with Ucn-2 treatment. Interestingly, Col3A1 LV mRNA expression was found to be decreased in ZSF1-Obese rats compared to ZSF1-Lean, and Ucn-2 therapy resulted in a faint further decrease of Col3A1 expression, compared to non-treated animals. Conclusion This work suggests that Ucn-2/CRHR2 system is altered in experimental HFpEF and that chronic administration of Ucn-2 attenuates LV dysfunction and remodeling, in particular the hypertrophic changes of the cardiac muscle. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Portuguese Foundation for Science and Technology (FCT), under the auspices of the Cardiovas-cular R&D Center–UnIC [UIDB/00051/2020 and UIDP/00051/2020] and project IMPAcT [PTDC/MED-FSL/31719/2017; POCI-01–0145-FEDER-031719].