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

• ClinicalTrials.gov Identifier: NCT02589977
• Recruitment Status: Completed
• First Posted: October 28, 2015
• Results First Posted: February 2, 2021
• Last Update Posted: February 2, 2021
• 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

• Study Type: Interventional
• Study Design: Allocation: Non-Randomized; Intervention Model: Factorial Assignment; Masking: None (Open Label); Primary Purpose: Diagnostic
• Conditions: Heart Failure, Diastolic; Diastolic Heart Failure; Hypertension
• Intervention: Drug: regadenoson
• Enrollment: 55

Participant Flow

Recruitment Details
Pre-assignment Details

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Period Title: Overall Study
Started	23	20	12
Completed	17	15	8
Not Completed	6	5	4

Baseline Characteristics

Arm/Group Title		Normal Participants	Hypertensive Participants	HFpEF Patients	Total
Arm/Group Description		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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants	Total of all reporting groups
Overall Number of Baseline Participants		17	15	8	40
Baseline Analysis Population Description		These are the people who attended baseline visit.
Age, Continuous; Median (Inter-Quartile Range); Unit of measure: Years
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
		57; (54 to 62)	58; (54 to 65)	69; (62 to 73)	58; (55 to 67)
Sex: Female, Male; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
	Female	12 70.6%	5 33.3%	7 87.5%	24 60.0%
	Male	5 29.4%	10 66.7%	1 12.5%	16 40.0%
Race (NIH/OMB); Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
	American Indian or Alaska Native	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Asian	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Native Hawaiian or Other Pacific Islander	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Black or African American	1 5.9%	0 0.0%	1 12.5%	2 5.0%
	White	16 94.1%	15 100.0%	7 87.5%	38 95.0%
	More than one race	0 0.0%	0 0.0%	0 0.0%	0 0.0%
	Unknown or Not Reported	0 0.0%	0 0.0%	0 0.0%	0 0.0%
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
United States	Number Analyzed	17 participants	15 participants	8 participants	40 participants
		17	15	8	40
Hypertension; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
		0 0.0%	15 100.0%	8 100.0%	23 57.5%
Diabetes; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
		0 0.0%	0 0.0%	3 37.5%	3 7.5%
BMI; Median (Inter-Quartile Range); Unit of measure: Kg/m^2
	Number Analyzed	17 participants	15 participants	8 participants	40 participants
		26.7; (22.6 to 28.7)	30.1; (27.8 to 35.7)	34.2; (29.9 to 37.8)	29.7; (25.6 to 33.0)

Outcome Measures

1. Primary Outcome

Title	Coronary Flow Reserve
Description	Rest and regadenoson stress coronary flow reserve by ammonia PET. Coronary flow calculated at rest and again at stress with coronary flow reserve calculated as the ratio of stress to rest coronary flow.
Time Frame	Baseline study visit

Outcome Measure Data

Analysis Population Description

Incomplete data for 18 because of either inability to complete scan OR scan quality not adequate for analysis.

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description:	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Overall Number of Participants Analyzed	10	6	6
Median (Inter-Quartile Range); Unit of Measure: ratio
	2.64; (2.34 to 2.85)	2.65; (2.56 to 3.11)	2.06; (1.96 to 2.26)

2. Secondary Outcome

Title	Myocardial Perfusion Reserve by CMR in Each Study Group.
Description	Myocardial perfusion reserve by CMR.
Time Frame	Baseline study visit.

Outcome Measure Data

Analysis Population Description

Incomplete data for 10 because of either inability to complete scan OR scan quality not adequate for analysis.

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description:	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Overall Number of Participants Analyzed	15	12	3
Median (Inter-Quartile Range); Unit of Measure: ratio
	2.19; (1.81 to 2.64)	1.74; (1.44 to 2.59)	1.29; (1.11 to 1.32)

3. Secondary Outcome

Title	Extracellular Volume (ECV) by CMR in Each Study Group
Description	Extracellular volume (ECV) by CMR.
Time Frame	Baseline study visit

Outcome Measure Data

Analysis Population Description

Incomplete data for 9 because of either inability to complete scan OR scan quality not adequate for analysis.

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description:	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Overall Number of Participants Analyzed	13	12	6
Median (Inter-Quartile Range); Unit of Measure: percent ECV
	31.9; (28.5 to 34.2)	29.2; (27.4 to 33.1)	30.9; (29.4 to 32.8)

4. Secondary Outcome

Title	Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group.
Description	Oxidative metabolism (Kmono/rate pressure product) by PET.
Time Frame	Baseline study visit

Outcome Measure Data

Analysis Population Description

Incomplete data for 4 because of either inability to complete scan OR scan quality not adequate for analysis.

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description:	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Overall Number of Participants Analyzed	16	14	6
Median (Inter-Quartile Range); Unit of Measure: min-1/(beats/min x mmhg)
	0.12; (0.10 to 0.13)	0.09; (0.07 to 0.11)	0.09; (0.09 to 0.10)

5. Secondary Outcome

Title	E/e' by Echo in Each Study Group.
Description	E/e' by echo. E is the transmitral peak velocity in early diastole. e' is the early diastolic tissue Doppler velocity average between the septal and lateral mitral annulus. E/e' is the ratio of these two values.
Time Frame	Baseline study visit

Outcome Measure Data

Analysis Population Description

We were able to collect data on all participants who completed the study.

Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description:	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Overall Number of Participants Analyzed	17	15	8
Median (Inter-Quartile Range); Unit of Measure: ratio
	7.2; (6.4 to 9.0)	8.2; (7.2 to 9.4)	13.0; (10.2 to 18.9)

Adverse Events

Time Frame	This is a cross sectional study. Subjects were followed for adverse events between screening/enrollment to one day following completion of the cardiac imaging study visit. Because this was not a longitudinal study with serial measurements of the end points the time between enrollment and cross sectional cardiac imaging study visit was variable for each subject in accordance with the study protocol. All subjects completed study procedures within thirteen months of enrollment.
Adverse Event Reporting Description	[Not Specified]
Arm/Group Title	Normal Participants	Hypertensive Participants	HFpEF Patients
Arm/Group Description	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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal 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. regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
All-Cause Mortality
	Normal Participants	Hypertensive Participants	HFpEF Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/23 (0.00%)	0/20 (0.00%)	0/12 (0.00%)
Serious Adverse Events
	Normal Participants	Hypertensive Participants	HFpEF Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/23 (0.00%)	0/20 (0.00%)	0/12 (0.00%)
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	0%
	Normal Participants	Hypertensive Participants	HFpEF Patients
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/23 (0.00%)	0/20 (0.00%)	0/12 (0.00%)

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Marvin Kronenberg, MD
• Organization: Vanderbilt University Medical Center
• Phone: 615-322-2318
• EMail: marvin.w.kronenberg@vumc.org

Publications of Results:

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.

• Responsible Party: Marvin W. Kronenberg, M.D., Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT02589977
• Other Study ID Numbers: 141686
• First Submitted: August 24, 2015
• First Posted: October 28, 2015
• Results First Submitted: December 23, 2020
• Results First Posted: February 2, 2021
• Last Update Posted: February 2, 2021