Inflammation: cause, consequence and therapeutic target in heart failure and related multi-organ dysfunction.

Heart failure with preserved ejection fraction (HFpEF) is a multi-organ syndrome with impairment of renal, respiratory and vascular systems. With a 5 year survival rate after its onset, HFpEF is a burden for society as none of the therapies has provided significant beneficial effects. We propose to characterize cellular and molecular components in the evolution to end-stage failure, and identify factors whose modulation at systemic and organ level may hold the premise to become novel biomarkers and therapeutic targets. We aim to address, in a model of HFpEF with multi-organ damage, multiple pathophysiological aspects in the heart, kidney, lung and vasculature: inflammation and macrophage polarization with a role of Wnt/β catenin and adenosine pathways; tissue remodeling and fibrosis; endothelial function and the modulation of NO/H2S pathways; renal pathophysiology and the role of potassium and chloride channels; the cross talk between immune system and cardiac stem cells engineered to produce specific growth factors (IGF-1, NRG-1, HGF, FGF-2, Activin and WNT-11) in the modulation of reparatory response after injury. Novel therapeutic strategies will be tested. We also aim to address sex-related specifications regarding the mechanisms and the therapeutic intervention.