Pilot Study to Evaluate the Effect of Inflammation in Heart Failure

• Status: Not yet recruiting
• Trial end date: 2024-08-28
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: National Heart, Lung, and Blood Institute (NHLBI)
• Treatments: Dapagliflozin

Criteria

• INCLUSION CRITERIA

Subjects of both genders will be considered for inclusion in this study. There will be no racial, ethnic, or gender discrimination.

Affected Subjects:

• 18years of age or older

• Diagnosed with HFpEF clinically confirmed by licensed physician or advanced practitioner

• Signs and symptoms of HFpEF

• LVEF >= 50% on echocardiography from screening visit

• Left ventricular hypertrophy (interventricular septal thickness (Bullet) 1cm) or enlarged left atrial volume ( (Bullet)34ml/m2) on echocardiography from screening visit

• NT-proBNP > 300pg/mL

Healthy Controls:

Females and males 18 years of age or older

EXCLUSION CRITERIA:

Affected Subjects:

• Pregnant or lactating women

• Acute coronary syndrome, cardiac surgery or percutaneous coronary intervention within past 6 months

• Atrial fibrillation

• Coronary artery disease with >= 50% stenosis in the left main, left anterior descending artery, left circumflex artery, or right coronary artery on CCTA from screening visit

• Infiltrative cardiomyopathy by diagnosis or imaging

-> Moderate valvular stenosis on screening echocardiography

• Diagnosis of an inflammatory disease (including psoriasis, psoriatic arthritis, rheumatoid arthritis, lupus, inflammatory bowel disease, HIV)

• Currently taking an SGLT2 inhibitor

• Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 body surface area according to the Modification of Diet in Renal Disease criteria

• Subjects with a contraindication to MRI scanning will not receive the CMR assessment.

These contraindications include subjects with the following devices:

i. Central nervous system aneurysm clips

ii. Implanted neural stimulator

iii. Implanted cardiac pacemaker or defibrillator

iv. Cochlear implant

v. Ocular foreign body (e.g. metal shavings)

vi. Implanted Insulin pump

vii. Metal shrapnel or bullet

• History of seizures or taking anti-epileptic medications

• History of serious hypersensitivity to dapagliflozin

• History of diabetic ketoacidosis

• Inability to provide informed consent

Healthy Controls:

• History of HF

• Acute coronary syndrome, cardiac surgery or percutaneous coronary intervention within past 6 months

• Coronary artery disease with >= 50% stenosis in the left main, left anterior descending artery, left circumflex artery, or right coronary artery on CCTA

• Diagnosis of an inflammatory disease (including psoriasis, psoriatic arthritis, rheumatoid arthritis, lupus, inflammatory bowel disease, HIV)

• Estimated glomerular filtration rate (eGFR) < 45 mL/min/1.73m^2 body surface area according to the Modification of Diet in Renal Disease criteria

• Pregnant women and lactating women

• Subjects with a contraindication to MRI scanning will not receive the CMR assessment.

These contraindications include subjects with the following devices:

viii. Central nervous system aneurysm clips

ix. Implanted neural stimulator

x. Implanted cardiac pacemaker or defibrillator

xi. Cochlear implant

xii. Ocular foreign body (e.g. metal shavings)

xiii. Implanted Insulin pump

xiv. Metal shrapnel or bullet

• History of seizures or taking anti-epileptic medications

• Inability to provide informed consent