Project Portugal 2030

Summary

We hypothesize that by activating the Ucn2/CRHR2 system in animals with HFpEF we might attenuate HFpEF and its comorbidities. Therefore, UroPE aims to investigate, with a translational approach, the role of the Ucn2/CRHR2 system in the pathophysiology of HFpEF, and to evaluate the efficacy of Ucn2 as a novel therapeutic strategy, as well as a diagnostic and prognostic tool in this syndrome. Specific goals of UroPE are to: 1. Determine changes in the expression of Ucn2 and its receptors, and of downstream signaling pathways in the heart and vascular tissue from an animal model of HFpEF; 2. Assess changes in: (i) cardiovascular function, in vivo (echocardiographic, exercise tolerance, blood pressure, and invasive hemodynamic studies), in vitro (isolated cardiomyocytes) and ex vivo (vascular studies), (ii) myocardial and vascular structure and histology and (iii) their patterns of gene expression, as well as (iv) the presence of circulating markers of HF, metabolic and renal dysfunction, in animals with HFpEF (and in their controls) with or without chronic Ucn2 treatment; 3. Study the Ucn2/CRHR2 system genic expression and Ucn2 functional effects in cardiac tissue samples collected from HFpEF human patients; 4. Investigate the potential role of Ucn2 circulating levels as a biomarker of diagnosis and as a predictor of HFpEF severity and outcome in human patients. UroPE will be carried out in a rat model of HFpEF, the obese Zucker diabetic fatty/Spontaneous hypertensive HF F1 (ZSF1) rat (19,20). The role of gender in HFpEF progression has been poorly explored. Thus, to gain insight into the role of gender in HFpEF development, to mimic the postmenopausal period associated with increased HFpEF incidence in women, and to unravel possible sex-specific Ucn2 effects, ovariectomized females will also be studied. We will study the effects of Ucn2 treatment in this animal model by monitoring invasive hemodynamic and echocardiographic parameters, blood pressure, exercise tolerance, metabolic parameters, in vitro cardiomyocytes and ex-vivo vascular performance, myocardial morphology and histology, changes in cardiac and vascular gene expression, immunolocation of Ucn2/CRHR2 signaling system components and plasma levels of HF, metabolic and renal dysfunction markers. Endpoints with potential therapeutic relevance include attenuation of HFpEF and of its comorbidities and improvement in cardiovascular structure and function. To translate our results into clinical practice, we will analyze UCN2/CRHR2 system gene expression, as well as the effects of the activation of this system on heart tissue samples from HFpEF patients. The discovery of novel biomarkers for HFpEF may allow for: more precise diagnosis and prevention by identifying individuals at highest risk, improved prognosis, identification of novel surrogate endpoints, selection of therapeutic targets, and development and evaluation of new therapies. Thus, Ucn2 plasma levels will be quantified in HFpEF patients and correlated with LV function and disease prognosis. With this task, we foresee a patent registration on the use of Ucn-2 blood levels as a diagnosis and prognosis biomarker in HFpEF. We expect to provide a comprehensive in-depth characterization of the pathophysiological effects of Ucn-2 in HFpEF, with mechanistic and phenotypic details, to unravel its therapeutic, diagnostic, and prognostic role in this syndrome and to translate our results to clinical practice.