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Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF (HFpEF-PRoF)

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ClinicalTrials.gov Identifier: NCT02589977
Recruitment Status : Recruiting
First Posted : October 28, 2015
Last Update Posted : May 9, 2019
Sponsor:
Collaborator:
Astellas Pharma US, Inc.
Information provided by (Responsible Party):
Marvin W. Kronenberg, M.D., Vanderbilt University Medical Center

Study Description
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Brief Summary:

Unlike heart failure with reduced ejection fraction (HFrEF) where several medicines and devices have been demonstrated to reduce mortality, no such therapies have been identified in HFpEF. This may be in part due to incomplete understanding of the underlying mechanisms of HFpEF.

Recently, impaired myocardial blood flow, reduced myocardial energy utilization, and increased myocardial fibrosis have been postulated to play important pathophysiologic roles in HFpEF. The investigators and others have demonstrated that HFrEF may be associated with altered myocardial energy utilization and "energy starvation." However, there are limited data regarding "energy starvation" in HFpEF and the relationships between myocardial blood flow, energy utilization, and fibrosis in HFpEF are largely unknown. Therefore, the purposes of this study are to use non-invasive cardiac imaging techniques to describe cardiac structure, function, blood flow, energetics, and fibrosis, and the relationships between these in order to better understand underlying mechanisms in HFpEF.


Condition or disease Intervention/treatment Phase
Heart Failure, Diastolic Diastolic Heart Failure Hypertension Drug: regadenoson Phase 4

Detailed Description:

The investigators hypothesize that HFpEF is associated with reductions in myocardial blood flow and energy utilization and increased myocardial fibrosis as compared to age and gender matched hypertensive and healthy controls. The investigators will test their hypotheses by comparing measurements of myocardial blood flow, energy utilization, and fibrosis between three subject groups (HFpEF vs hypertension vs healthy). Myocardial blood flow will be quantitated from nitrogen (N)13-Ammonia positron emission tomography (PET) and gadolinium enhanced cardiac magnetic resonance (CMR) imaging, both at rest and stress following coronary vasodilation with regadenoson. Myocardial energy utilization will be quantified with 11C-acetate PET imaging and myocardial fibrosis will be assessed with gadolinium enhanced CMR and alterations in myocardial T1. Echocardiography will be utilized to quantify cardiac diastolic function.

It is anticipated that the results of this proposed study will provide a foundation that will inform future studies aimed at identifying novel preventive or therapeutic agents in HFpEF.


Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF
Study Start Date : November 2015
Estimated Primary Completion Date : May 2020
Estimated Study Completion Date : August 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Regadenoson

Arms and Interventions
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Arm Intervention/treatment
normal participants

No cardiovascular abnormalities or diabetes. Estimated glomerular filtration rate (eGFR) >60.

Studies: Echocardiography for left ventricular function and LV diastolic performance; cardiac magnetic resonance (CMR) imaging using gadolinium for LV fibrosis and regadenoson for myocardial blood flow (MBF); positron-emission tomography (PET) using regadenoson for MBF and 11C-acetate for oxidative metabolism.

 Drug: regadenoson
evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Other Names:
  • positron emission tomography
  • echocardiography
  • cardiac magnetic resonance imaging
hypertensive participants

No history of coronary artery disease or diabetes. Estimated glomerular filtration rate (eGFR) >60.

Studies: Echocardiography for left ventricular function and LV diastolic performance; cardiac magnetic resonance (CMR) imaging using gadolinium for LV fibrosis and regadenoson for myocardial blood flow (MBF); positron-emission tomography (PET) using regadenoson for MBF and 11C-acetate for oxidative metabolism.

 Drug: regadenoson
evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Other Names:
  • positron emission tomography
  • echocardiography
  • cardiac magnetic resonance imaging
HFpEF patients

No history of coronary artery disease or diabetes. Estimated glomerular filtration rate (eGFR) >60.

Studies: Echocardiography for left ventricular function and LV diastolic performance; cardiac magnetic resonance (CMR) imaging using gadolinium for LV fibrosis and regadenoson for myocardial blood flow (MBF); positron-emission tomography (PET) using regadenoson for MBF and 11C-acetate for oxidative metabolism.

 Drug: regadenoson
evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Other Names:
  • positron emission tomography
  • echocardiography
  • cardiac magnetic resonance imaging


Outcome Measures
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Primary Outcome Measures :
  1. Enumerate subjects with "myocardial energy starvation" among patients with HFpEF vs. hypertensive and normal subjects, using myocardial blood flow on CMR and PET, oxidative metabolism (11C-acetate) and interstitial fibrosis on CMR, a composite outcome. [ Time Frame: 3 years ]
    rest and regadenoson stress myocardial blood flow in each study group, using CMR and PET, oxidative metabolism using 11C-acetate and interstitial fibrosis on CMR. The criterion for defining "energy starvation" is the combination of abnormal myocardial blood flow on CMR or PET, abnormal values for fibrosis on CMR and abnormally low oxidative metabolic rate.


Secondary Outcome Measures :
  1. number of participants with abnormalities of myocardial blood flow (MBF) by CMR in each study group and between study groups [ Time Frame: 3 years ]
    as noted above

  2. number of participants with abnormalities of myocardial blood flow (MBF) by PET in each study group and between study groups [ Time Frame: 3 years ]
    as noted above

  3. number of participants with abnormalities of fibrosis in each study group and between groups [ Time Frame: 3 years ]
    as noted above

  4. number of participants with abnormalities of oxidative metabolism in each study group and between groups [ Time Frame: 3 years ]
    as noted above

  5. number of participants with abnormal echocardiographic findings between and among the 3 study groups [ Time Frame: 3 years ]
    comparison of LV ejection fraction and Doppler indices of LV diastolic performance among the 3 study groups

  6. number of participants with abnormal myocardial blood flow and fibrosis by CMR and and abnormal oxidative metabolism vs. echocardiographic indices of LV performance. [ Time Frame: 3 years ]
    as above

  7. number of participants with abnormal myocardial blood flow by PET and fibrosis by CMR and abnormal oxidative metabolism vs. echocardiographic indices of LV performance. [ Time Frame: 3 years ]
    as above


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   50 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   Yes
Criteria

ALL

Inclusion Criteria:

  • estimated glomerular filtration rate (eGFR) > 60 ml/min
  • preserved left ventricular ejection fraction (>= 50%) on echocardiography

Exclusion Criteria:

  • coronary artery disease
  • diabetes mellitus
  • contraindications to cardiac magnetic resonance imaging (CMR)
  • weight >350 lbs
  • inability to lie flat for imaging
  • anemia
  • contraindications to regadenoson or aminophylline

HEALTHY

Inclusion criteria:

  • normal cardiac structure and function on echocardiography
  • BP < 140/90

Exclusion criteria:

  • known cardiovascular disease, cardiac risk factors or use of cardiac medications

HYPERTENSIVE

Inclusion criteria:

  • history of BP >140/90
  • 1 or more antihypertensive medications
  • LV ejection fraction (LVEF) at least 50%
  • current BP < 160/90

Exclusion criteria:

  • known cardiovascular disease or risk factors aside from hypertension or use of cardiac medications

HFpEF

Inclusion criteria:

  • physician-confirmed diagnosis of HF
  • symptomatic HF
  • LVEF at least 50%
  • elevated LV filling pressure by catheterization, echocardiographic criteria or B-type-natriuretic peptide > 100
  • current BP < 160/90

Exclusion criteria:

  • prior history of LVEF below 50%
  • acute decompensated HF
  • moderate or greater valvular disease
  • significant cardiac arrhythmias
  • pericardial disease
  • congenital heart disease
  • primary pulmonary hypertension
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02589977


Contacts
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Contact: Marvin W Kronenberg, MD 615-322-8822 marvin.w.kronenberg@vanderbilt.edu
Contact: Deepak K Gupta, MD 615-936-2530 d.gupta@vanderbilt.edu

Locations
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United States, Tennessee
Vanderbilt University Medical Center Recruiting
Nashville, Tennessee, United States, 37232
Contact: Marvin W Kronenberg, MD    615-322-8822    marvin.w.kronenberg@vanderbilt.edu   
Contact: Deepak K Gupta, MD    615-936-2530    deepak.gupta@vanderbilt.edu   
Principal Investigator: Marvin Kronenberg, MD         
Sponsors and Collaborators
Marvin W. Kronenberg, M.D.
Astellas Pharma US, Inc.
Investigators
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Principal Investigator: Marvin W Kronenberg, MD Vanderbilt University
More Information
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Publications of Results:

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Responsible Party: Marvin W. Kronenberg, M.D., Professor of Medicine and Radiology, Vanderbilt University Medical Center
ClinicalTrials.gov Identifier: NCT02589977     History of Changes
Other Study ID Numbers: 141686
First Posted: October 28, 2015    Key Record Dates
Last Update Posted: May 9, 2019
Last Verified: May 2019

Keywords provided by Marvin W. Kronenberg, M.D., Vanderbilt University Medical Center:
magnetic resonance imaging
positron-emission tomography
echocardiography
myocardial blood flow
energy metabolism

Additional relevant MeSH terms:
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Heart Failure
Heart Failure, Diastolic
Heart Diseases
Cardiovascular Diseases
Regadenoson
Adenosine A2 Receptor Agonists
 Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs