Pathophysiological and therapeutic implications of urocortin-2 in heart failure with preserved ejection fraction

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