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
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 miniswine 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 ultrasound 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.