Search

Pulmonary arterial hypertension (PAH), is a chronic disorder characterized by excessive pulmonary vascular remodelling, resulting in elevated pulmonary vascular resistance and right ventricle (RV) overload and failure. PAH remains incurable, and new therapeutic approaches are required. The microRNA-146a (miR-146a) promotes vascular smooth muscle cell proliferation and vascular neointimal hyperplasia, both important hallmarks of PAH. This study aimed to investigate the role of miR-146a in the pathophysiology of PAH and in the progression to RV hypertrophy and failure. Sprague Dawley rats received a subcutaneous injection of monocrotaline (MCT group) or vehicle (CTRL group) and, after fourteen days they were treated, by intratracheal nebulization, with an anti-miR-146a, forming four distinct groups: CTRL-treated; CTRL-untreated, MCT-treated, and MCT-untreated. Twenty-seven days after MCT injection, echocardiographic and invasive hemodynamic evaluations were performed in all animal groups. Also, wild-type (WT) and miR-146a knock-out (KO) (miR-146a−/−) mice were submitted to either 3 weeks of chronic hypoxia-induced PAH with weekly Sugen 5416 administration (SuHx). Compared to MCT-untreated rats, the MCT-treated rats showed decreased RV hypertrophy, (as measured by the Fulton index),decreased RV end-diastolic diameter/left ventricle end-diastolic diameter (RVEDD/LVEDD) ratio, and decreased in RV diastolic pressures. KO-SuHx group, when compared to WT-SuHx group, showed decreased RV hypertrophy (as measured by the Fulton index), and decreased RV systolic pressures and dilation, as well as lower RV end end-diastolic diameter (RVEDDi) and right atria area (RAAi). Our findings show that miR-146a pharmacological or genetic inhibition reduces RV remodelling and improves cardiac function. Thus, miR-146a represents a promising therapeutic target in PAH. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): This research was supported by the Portuguese Foundation for Science and Technology (FCT).

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].

Urocortin (Ucn)-2 has shown promising therapeutic effects on heart failure (HF). However, there are still significant knowledge gaps regarding the role and modulation of the endogenous Ucn-2 axis in the cardiovascular system and, specifically, in acute HF. We evaluated Ucn-2 levels in admission serum samples of 80 acute HF patients and assessed their association with clinical, analytical and echocardiographic parameters. Median age was 76.5 years, and 37 patients (46%) were male. Median serum Ucn-2 was 2.3ng/mL. Ucn-2 levels were positively associated with peripheral edemas (P = 0.022), hepatomegaly (P = 0.007) and sodium retention score (ρ = 0.37, P = 0.001) and inversely correlated with inferior vena cava collapse at inspiration (ρ = -0.37, P = 0.001). Additionally, patients with higher Ucn-2 levels had a higher prevalence of right atrial dilation (P = 0.027), right ventricle dilation (P = 0.008), and higher systolic pulmonary artery pressure (ρ = 0.34, P = 0.002). Regarding analytical parameters, Ucn-2 correlated positively with log BNP (r = 0.22, P = 0.055) and inversely with uric acid (r = 0.24, P = 0.029) and total (r = -0.30, P = 0.007) and low-density lipoprotein cholesterol (r = -0.23, P = 0.038). No associations were found between Ucn-2 and age, sex or left heart structure or function. In conclusion, Circulating Ucn-2 was associated with clinical and echocardiographic markers of volume overload and pulmonary hypertension in acute HF patients.