# Mechanistic underpinnings of increased adipose tissue in HFpEF

> **NIH NIH R01** · BOSTON UNIVERSITY MEDICAL CAMPUS · 2020 · $663,147

## Abstract

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.

## Key facts

- **NIH application ID:** 9944667
- **Project number:** 5R01HL145985-02
- **Recipient organization:** BOSTON UNIVERSITY MEDICAL CAMPUS
- **Principal Investigator:** Flora Sam
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $663,147
- **Award type:** 5
- **Project period:** 2019-07-01 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9944667

## Citation

> US National Institutes of Health, RePORTER application 9944667, Mechanistic underpinnings of increased adipose tissue in HFpEF (5R01HL145985-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9944667. Licensed CC0.

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