1)Characterise the cardiometabolic role of SIRT1/PGC-1a/FGF21 axis in HFpEF (TASK 1);
2)Assess the role and therapeutic potential of FGF21 in HFpEF (2-hit male and 4-hit female model) imposed on FGF21-KO mice (loss of function) or upon FGF21 treatment (gain of function). We will assess plasma infl ammation and oxidative stress, metabolic (PET-scan) and functional changes (echocardiography) during HFpEF progression and FGF21-signalling changes, autophagic flux, myocardial proteomic and metabolomic changes, mitochondrial function and energy substrate preferences (TASK 2);
3)Dissect the role of SIRT1/PGC-1a/FGF21/AMPK on the metabolic changes taking place in HFpEF upon SGLT2i by using the FGF21-KO or wildtype HFpEF mice (TASK 3) addressing the same parameters as in TASKs 1-2;
4)Dissect the role of SIRT1/PGC-1a/FGF21 on the metabolic changes induced by SGLT2i chronic treatment of HFpEF mice, assessing the molecular, histological and functional (using living myocardial slices) changes (TASK 3);
5)Characterise the cardiac functional and metabolic profi le of HFpEF patients stratifi ed according to systemic FGF21 levels before and after 6 months of SGLT2i treatment (TASKs 4-5). This includes assessing cardiac morphofunctional changes by echocardiography, the metabolic status (data derived from preexisting PET-scans, bioimpedance, oral glucose tolerance (OGTT) and insulin resistance (IR) tests), infl ammation levels as well as proteome and metabolome profi les using HFpEF patients' myocardial biopsies.
6)Assess FGF21 biomarker value for functional improvement of HFpEF patients with or without SGLT2i treatment. The 6-minute walk test will be evaluated as the primary outcome. Other secondary outcomes will include cardiac remodelling (echocardiographic and histological parameters, BNP, NT-proBNP) and metabolic status (PET imaging in a subset of patients). A data subanalysis will allow for assessing the impact of SGLT2i, sex, age and HFpEF phenogroup on FGF21 levels (TASK 5).
7)Disseminate results among different societal actors and stakeholders (TASK 6). |
