Heart failure (HF) is a highly prevalent syndrome of impaired cardiac function that constitutes the main cause of hospitalization and disability amongst the elderly, a leading cause of mortality, morbidity and resource consumption. HF with preserved ejection fraction (HFpEF) is characterized by preserved ejection, impaired cardiac filling, lung congestion and effort intolerance, accounting for a rising proportion of over 50% of cases due to ageing and increasing incidences of systemic arterial hypertension (SAH), obesity and diabetes mellitus (DM). The current proposal sets forth to address this issue by a mixed strategy of discovery science approach through comprehensive multi-omics studies in plasma and tissues from HFpEF patients and animal models with and without comorbidities (DM, SAH and obesity), and an hypothesis-driven approach focusing on disturbances of cell function and communication in endothelial cells (EC), cardiac fibroblasts (CF), adipocytes and CM. A holistic view of HFpEF and of the role of comorbidities will be achieved by correlating and integrating transcriptomics, proteomics and lipidomics studies with clinical data. The impact on CM and myocardium will be comprehensively assessed in vitro and in vivo. Finally, preclinical testing of functional foods, synthetic antioxidants, enhanced bioavailability putative therapeutic molecules as well as other potentially effective gene targets identified along the project’s course will be assayed.