Pilot Study to Evaluate the Effect of Inflammation in Heart Failure
Status:
Not yet recruiting
Trial end date:
2024-08-28
Target enrollment:
Participant gender:
Summary
Study Description:
Heart failure (HF) remains a significant public health burden. Unlike heart failure with
reduced ejection fraction (HFrEF), heart failure with preserved ejection fraction (HFpEF)
currently does not have any effective therapies, suggesting incomplete understanding of the
underlying mechanisms of the syndrome. Chronic inflammation has been postulated to be one of
the central mechanisms in HFpEF pathogenesis. In this pilot study to be conducted at the NIH
Clinical Center, we propose to examine the role of the NLRP3 inflammasome- IL-1 pathway in
HFpEF and evaluate whether treatment using the sodium glucose co-transport 2 (SGLT2)
inhibitor dapagliflozin can attenuate NLRP3 inflammasome activation.
Objectives:
- To test the hypothesis that macrophage NLRP3 inflammasomeactivation is upregulated in
subjects with HFpEF compared to healthy controls and that NLRP3 inflammasome activation
will be attenuated by dapagliflozin therapy
- To test the hypothesis that pro-inflammatory signatures in peripheral blood mononuclear
cells (PBMCs) will be increased in HFpEF compared to healthy controls and that they will
be attenuated by dapagliflozin therapy
- To test the hypothesis that macrophage NLRP3 inflammasome activation associates with
perturbances in myocardial perfusion, structure, and function and that attenuation of
NLRP3 inflammasome activation with dapagliflozin therapy will associate with improvement
in myocardial perfusion, myocardial structure, and function
- To test the hypothesis that NLRP3 inflammasome activation is inversely associated with
maximum oxygen consumption (VO2max), exercise functional status, and symptoms in HFpEF
and that attenuation of NLRP3 inflammasome activation with dapagliflozin therapy will
associate with improvement in VO2max, exercise functional status, and symptoms.
Endpoints:
Primary outcome will be:
- IL-1 beta, a measure of NLRP3 inflammasome activation, from macrophages in subjects with
HFpEF compared to healthy controls.
Secondary outcomes will be:
- Delineation of the differences in PBMC gene expression profiles measured by RNA
sequencing and in immunophenotyping signatures measured by flow cytometry in subjects
with HFpEF compared to healthy controls. The effect of dapagliflozin on these
immunological profiles will also be determined in the HFpEF study subjects.
- Myocardial perfusion (on CMR), left ventricular mass (on CMR), diastolic function (on
echocardiogram), myocardial mechanics (on echocardiogram and CMR), myocardial edema and
inflammation, and interstitial fibrosis (on CMR) in subjects with HFpEF compared to
healthy controls and in response to dapagliflozin therapy.
Exploratory outcomes will be:
- VO2max, symptoms and exercise functional status in HFpEF compared to healthy controls
and in response to dapagliflozin therapy.