Heart failure (HF) is the major diagnosis in >1 million hospitalizations annually, with “HF with preserved ejection fraction” (HFpEF), accounting for up to 50% of all clinical HF presentations. Yet, despite this and its impact on escalating health care costs, there are no evidence-based therapies for HFpEF. This stems, in part, from a lack of mechanistic understanding about the pathogenesis of HFpEF and that a more tailored, personalized approach is needed for HFpEF. Large outcome trials and registries reveal that HFpEF is a heterogeneous phenotype and being overweight/obese is a major risk factor (70-84%). Likewise, ~45% of patients with HFpEF are obese and obesity, in itself, is associated with the future development of HF despite adjusting for established risk factors. Increased adiposity in obesity promotes inflammation and hypertension which may contribute to HFpEF pathophysiology. Brown adipose tissue (BAT) plays a pivotal role in regulating whole-body energy balance. In both rodents and humans, there are two types of thermogenic adipocytes: classical brown adipocytes and beige/“brite” adipocytes. The latter are BAT that appears among white adipose tissue in response to a stimulus through a process termed “browning”. “Browning” was recently shown to occur in lean, metabolically healthy HFpEF mice but the relevance and translational implications of these findings are unknown since browning may be activated in response to stressors, such as cancer-associated cachexia or massive burns. Therefore it is unknown whether browning is deleterious or an adaptive stress response and whether it may serve as a therapeutic target for obesity-associated diseases, such as HFpEF. The broad objective of this translational proposal is therefore to dissect the regulation of browning in white adipose tissue in HFpEF and to explore the clinical relevance of these findings. We will explore 2 specific aims: Aim 1: To investigate in patients with obese HFpEF, the relationship between adipose tissue browning and angiogenesis and how these correlate with acute clinical decompensation and HFpEF progression. In a longitudinal, prospective study in obese patients with HFpEF, acute HFpEF decompensation (defined as a hospital admission) is associated with: (i) increased browning in subcutaneous white adipose tissue, (ii) increased circulating levels of pro-angiogenic factors (VEGF-A and ANG-1) and decreased anti-angiogenic factors (ANGPTL-4 and ANG-2) and (iii) changes in angiogenic factors during the acute HF admission, associates with clinical outcomes defined as worsened LV diastolic dysfunction, acute clinical decompensation and predicts time-to-readmission. Aim 2: To investigate the role of HFpEF in browning and angiogenesis in adipose tissue and the effect of increased browning activation on HFpEF progression in obese ZSF1 rats.

Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for up to 50% of all HF presentations; but despite increasing prevalence, morbidity and mortality there remains a glaring lack of evidence-based therapies. There is an incomplete understanding of the pathobiological mechanisms of HFpEF and its progression to overt clinical HF. The impact of our proposed studies is high, as they will advance our knowledge of the contribution of adipose tissue and excess adiposity to HFpEF pathogenesis and identify possible novel targets for future therapies in HFpEF.