PROJECT SUMMARY Heart failure with preserved ejection fraction (HFpEF) has emerged as a significant unmet medical need in cardiovascular medicine and 60% of all new heart failure diagnoses are HFpEF. The increasing prevalence of HFpEF coupled with a complete lack of effective FDA approved treatments further accentuates this critical public health problem. It is well appreciated that chronic over-activation of the sympathetic nervous system promotes left ventricular (LV) hypertrophic remodeling and fibrosis, profound endothelial and vascular injury, and renal dysfunction. The proposed studies will evaluate the beneficial effects of renal denervation (RDN) on left ventricular and vascular function in a novel swine model of HFpEF. HFpEF will be induced in Göttingen mini-swine following chronic treatment with deoxycorticosterone acetate (DOCA) combined with a Western Diet that induces hypertension and metabolic syndrome followed by LV diastolic dysfunction, pulmonary congestion, exercise intolerance, and clinically relevant HFpEF. RDN will be performed following the onset of HFpEF utilizing a clinical RDN catheter system that employs RF energy to destroy the renal sympathetic nerves. The Central Hypothesis of the proposed studies is that RDN therapy will promote myocardial repair and attenuate HFpEF progression via downregulation of pathological signaling in the kidney and heart. Specific Aim 1 is to determine the effects of RDN therapy on heart failure progression and severity in a clinically relevant large animal model of HFpEF. Specific Aim 2 is to identify candidate cardiac and extra-cardiac mediators that underlie the cardioprotective effects of RDN using genomic, metabolomic, and proteomic approaches. These studies will determine if RDN ameliorates the severity and progression of HFpEF and explore the mechanisms by which RDN exerts cardioprotective and vascular protective effects. These studies will involve an array of physiological, biochemical, genomic, metabolomic, and proteomic approaches to assess the potential efficacy of RDN in HFpEF. Results from these studies will significantly extend our current understanding of the pathobiology of HFpEF and provide critical information that helps to guide the development of novel therapies to treat patients that suffer from HFpEF.