The Effect of Inflammation in Heart Failure

Sponsor

National Heart, Lung, and Blood Institute (NHLBI) (NIH)

Overall Status

Withdrawn

CT.gov ID

NCT05330013

Collaborator

(none)

Enrollment

Location

Arms

Study Details

Study Description

Brief Summary

Background:

Heart failure is a serious health condition. Researchers believe inflammation plays a role. They want to see if adding an additional heart drug to a person s treatment can help treat heart failure with preserved ejection fraction (HFpEF).

Objective:

To learn if chronic inflammation is high in heart failure and if taking dapagliflozin along with the standard of care medicines for 6 months will reduce inflammation and improve heart function in people with HFpEF.

Eligibility:

People aged 18 and older who have heart failure and qualify for dapagliflozin therapy. Healthy adult volunteers are also needed.

Design:

Participants will be screened with:
Medical history
Physical exam
Heart function tests
X-ray scans of the heart and blood vessels. They may receive medicines to slow their heart rate or make their heart blood vessels bigger. An intravenous (IV) catheter will be placed in their arm to inject contrast.
Blood and urine tests
Participants will have up to 3 study visits. Some screening tests will be repeated.

Participants will take one tablet of the study drug daily for 6 months.

-Participants will have an imaging scan of their heart and blood vessels. They will receive a contrast and stress medicine through an IV to view blood supply.

Participants will have a stress test that measures exercise ability. They will wear sticky pads on their chest, a blood pressure cuff, and a mask. They will also have a 6-Minute Walk Test.

Participants will complete questionnaires about their symptoms and their health.

Participants may be on the study for up to 6 months. They will have a follow-up phone call 1 month after treatment ends.

...

Condition or Disease	Intervention/Treatment	Phase
Myocardial Dysfunction Heart Failure Inflammation	Drug: Dapagliflozin Device: MRI scan Device: CMR imaging	Phase 2

Detailed Description

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

0 participants

Allocation:

Non-Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Basic Science

Official Title:

Pilot Study to Evaluate the Effect of Inflammation in Heart Failure

Actual Study Start Date :

Jun 23, 2022

Actual Primary Completion Date :

Jun 23, 2022

Actual Study Completion Date :

Jun 23, 2022

Arms and Interventions

Arm	Intervention/Treatment
Other: Control Healthy volunteers who are age and sex matched	Device: MRI scan For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements). Device: CMR imaging Enrolled subjects will undergo stress vasodilator and rest perfusion CMR
Experimental: Subjects with HFpEF Subjects are defined as patients with a diagnosis of HFpEF clinically confirmed by a licensed physician or advanced practitioner who meet the inclusion and exclusion criteria and are able to provide informed consent.	Drug: Dapagliflozin Subjects will be instructed to take dapagliflozin 10 mg once daily for 6 months (with or without food). Device: MRI scan For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements). Device: CMR imaging Enrolled subjects will undergo stress vasodilator and rest perfusion CMR

Arm

Intervention/Treatment

Other: Control

Healthy volunteers who are age and sex matched

Device: MRI scan

For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements).

Device: CMR imaging

Enrolled subjects will undergo stress vasodilator and rest perfusion CMR

Experimental: Subjects with HFpEF

Subjects are defined as patients with a diagnosis of HFpEF clinically confirmed by a licensed physician or advanced practitioner who meet the inclusion and exclusion criteria and are able to provide informed consent.

Drug: Dapagliflozin

Subjects will be instructed to take dapagliflozin 10 mg once daily for 6 months (with or without food).

Device: MRI scan

For subjects, depending on the subject's heart rate, base, mild, or apex short-axis slices will be acquired during the first pass of the contract (60 measurements).

Device: CMR imaging

Enrolled subjects will undergo stress vasodilator and rest perfusion CMR

Outcome Measures

Primary Outcome Measures

IL-1 beta levels [6 months]
IL-1 beta, a measure of NLRP3 inflammasome activation, from macrophages in subjects with HFpEF compared to healthy controls

Secondary Outcome Measures

Change in CMR, ECHO in affected vs healthy individuals [2.5 years]
1. Myocardial perfusion(CMR), 2. Left ventricular mass(CMR), 3. Diastolic function (ECHO), 4. Myocardial mechanics (ECHO, CMR), 5. Myocardial edema and inflammation, and interstitial fibrosis(CMR) Compared to both group and in response to dapagliflozin therapy
Immunological profiles in affected vs healthy individuals [2.5 years]
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

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years to 90 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Yes

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:

Central nervous system aneurysm clips
Implanted neural stimulator
Implanted cardiac pacemaker or defibrillator
Cochlear implant
Ocular foreign body (e.g. metal shavings)
Implanted Insulin pump
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.