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

• Sponsor: Marvin W. Kronenberg, M.D.
• Collaborator: Astellas Pharma US, Inc.
• Information provided by (Responsible Party): Marvin W. Kronenberg, M.D., Vanderbilt University Medical Center

Tracking Information

• First Submitted Date: August 24, 2015
• First Posted Date: October 28, 2015
• Last Update Posted Date: May 9, 2019
• Study Start Date: November 2015
• Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: October 28, 2015)

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.

Original Primary Outcome Measures (submitted: October 27, 2015)

Enumerate participants meeting criteria for "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. [ 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.

• Change History: Complete list of historical versions of study NCT02589977 on ClinicalTrials.gov Archive Site

Current Secondary Outcome Measures (submitted: October 28, 2015)

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

Original Secondary Outcome Measures (submitted: October 27, 2015)

• number of participantswith abnormalities of myocardial blood flow (MBF) by CMR in each study group and between study groups [ Time Frame: 3 years ]
  as noted above
• 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
• number of participants with abnormalities of fibrosis in each study group and between groups [ Time Frame: 3 years ]
  as noted above
• number of participants with abnormalities of oxidative metabolism in each study group and between groups [ Time Frame: 3 years ]
  as noted above
• 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
• 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
• 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

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF
• Official Title: Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF

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.

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 Type: Interventional
• Study Phase: Phase 4
• Study Design: Allocation: Non-Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic

Condition

• Heart Failure, Diastolic
• Diastolic Heart Failure
• Hypertension

Intervention

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

Study Arms

• 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.

  Intervention: Drug: regadenoson
• 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.

  Intervention: Drug: regadenoson
• 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.

  Intervention: Drug: regadenoson

Publications *

• Bell SP, Adkisson DW, Ooi H, Sawyer DB, Lawson MA, Kronenberg MW. Impairment of subendocardial perfusion reserve and oxidative metabolism in nonischemic dilated cardiomyopathy. J Card Fail. 2013 Dec;19(12):802-10. doi: 10.1016/j.cardfail.2013.10.010. Epub 2013 Oct 29.
• Gupta DK, Shah AM, Castagno D, Takeuchi M, Loehr LR, Fox ER, Butler KR, Mosley TH, Kitzman DW, Solomon SD. Heart failure with preserved ejection fraction in African Americans: The ARIC (Atherosclerosis Risk In Communities) study. JACC Heart Fail. 2013 Apr;1(2):156-63.

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: October 27, 2015): 60
• Original Estimated Enrollment: Same as current
• Estimated Study Completion Date: August 2020
• Estimated Primary Completion Date: May 2020 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 50 Years to 75 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

Contacts

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

• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02589977
• Other Study ID Numbers: 141686
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Responsible Party: Marvin W. Kronenberg, M.D., Vanderbilt University Medical Center
• Study Sponsor: Marvin W. Kronenberg, M.D.
• Collaborators: Astellas Pharma US, Inc.

Investigators

• Principal Investigator: Marvin W Kronenberg, MD; Vanderbilt University

• PRS Account: Vanderbilt University Medical Center
• Verification Date: May 2019