Diastolic Heart Failure, Heart Failure, Diastolic, Hypertension
Conditions
Keywords
magnetic resonance imaging, positron-emission tomography, echocardiography, myocardial blood flow, energy metabolism
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.
Interventions
DRUGregadenoson
evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants
Sponsors
Astellas Pharma US, Inc.
Marvin W. Kronenberg, M.D.
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
DIAGNOSTIC
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
50 Years to 75 Years
Healthy volunteers
Yes
Inclusion 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Coronary Flow Reserve | Baseline study visit | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Myocardial Perfusion Reserve by CMR in Each Study Group. | Baseline study visit. | Myocardial perfusion reserve by CMR. |
| Extracellular Volume (ECV) by CMR in Each Study Group | Baseline study visit | Extracellular volume (ECV) by CMR. |
| Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group. | Baseline study visit | Oxidative metabolism (Kmono/rate pressure product) by PET. |
| E/e' by Echo in Each Study Group. | Baseline study visit | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants | 17 |
| 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.
regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants | 15 |
| 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.
regadenoson: evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants | 8 |
| Total | 40 |
Baseline characteristics
| Characteristic | Hypertensive Participants | Total | Normal Participants | HFpEF Patients |
|---|---|---|---|---|
| Age, Continuous | 58 years | 58 years | 57 years | 69 years |
| BMI | 30.1 kg/m^2 | 29.7 kg/m^2 | 26.7 kg/m^2 | 34.2 kg/m^2 |
| Diabetes | 0 Participants | 3 Participants | 0 Participants | 3 Participants |
| Hypertension | 15 Participants | 23 Participants | 0 Participants | 8 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 15 Participants | 38 Participants | 16 Participants | 7 Participants |
| Region of Enrollment United States | 15 participants | 40 participants | 17 participants | 8 participants |
| Sex: Female, Male Female | 5 Participants | 24 Participants | 12 Participants | 7 Participants |
| Sex: Female, Male Male | 10 Participants | 16 Participants | 5 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 23 | 0 / 20 | 0 / 12 |
| other Total, other adverse events | 0 / 23 | 0 / 20 | 0 / 12 |
| serious Total, serious adverse events | 0 / 23 | 0 / 20 | 0 / 12 |
Outcome results
Primary
Coronary Flow Reserve
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
Population: Incomplete data for 18 because of either inability to complete scan OR scan quality not adequate for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Participants | Coronary Flow Reserve | 2.64 ratio |
| Hypertensive Participants | Coronary Flow Reserve | 2.65 ratio |
| HFpEF Patients | Coronary Flow Reserve | 2.06 ratio |
Secondary
E/e' by Echo in Each Study Group.
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
Population: We were able to collect data on all participants who completed the study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Participants | E/e' by Echo in Each Study Group. | 7.2 ratio |
| Hypertensive Participants | E/e' by Echo in Each Study Group. | 8.2 ratio |
| HFpEF Patients | E/e' by Echo in Each Study Group. | 13.0 ratio |
Secondary
Extracellular Volume (ECV) by CMR in Each Study Group
Extracellular volume (ECV) by CMR.
Time frame: Baseline study visit
Population: Incomplete data for 9 because of either inability to complete scan OR scan quality not adequate for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Participants | Extracellular Volume (ECV) by CMR in Each Study Group | 31.9 percent ECV |
| Hypertensive Participants | Extracellular Volume (ECV) by CMR in Each Study Group | 29.2 percent ECV |
| HFpEF Patients | Extracellular Volume (ECV) by CMR in Each Study Group | 30.9 percent ECV |
Secondary
Myocardial Perfusion Reserve by CMR in Each Study Group.
Myocardial perfusion reserve by CMR.
Time frame: Baseline study visit.
Population: Incomplete data for 10 because of either inability to complete scan OR scan quality not adequate for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Participants | Myocardial Perfusion Reserve by CMR in Each Study Group. | 2.19 ratio |
| Hypertensive Participants | Myocardial Perfusion Reserve by CMR in Each Study Group. | 1.74 ratio |
| HFpEF Patients | Myocardial Perfusion Reserve by CMR in Each Study Group. | 1.29 ratio |
Secondary
Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group.
Oxidative metabolism (Kmono/rate pressure product) by PET.
Time frame: Baseline study visit
Population: Incomplete data for 4 because of either inability to complete scan OR scan quality not adequate for analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Normal Participants | Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group. | 0.12 min-1/(beats/min x mmhg) |
| Hypertensive Participants | Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group. | 0.09 min-1/(beats/min x mmhg) |
| HFpEF Patients | Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group. | 0.09 min-1/(beats/min x mmhg) |