Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF

Study Overview
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Brief Summary
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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
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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.

Official Title
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Myocardial Perfusion, Oxidative Metabolism, and Fibrosis in HFpEF

Conditions
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Heart Failure, Diastolic, Diastolic Heart Failure, Hypertension

Intervention / Treatment
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* Drug: regadenoson


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 50 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Non-Randomized
Intervention Model: Factorial Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: normal participants<br>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<br>* evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants<br>* Other names: cardiac magnetic resonance imaging;|
| Other: hypertensive participants<br>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<br>* evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants<br>* Other names: cardiac magnetic resonance imaging;|
| Other: HFpEF patients<br>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<br>* evaluation of myocardial blood flow, interstitial fibrosis and oxidative metabolism in HFpEF, compared to hypertensive and normal participants<br>* Other names: cardiac magnetic resonance imaging;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Baseline study visit | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Myocardial Perfusion Reserve by CMR in Each Study Group. | Myocardial perfusion reserve by CMR. | Baseline study visit. | 
| Extracellular Volume (ECV) by CMR in Each Study Group | Extracellular volume (ECV) by CMR. | Baseline study visit | 
| Oxidative Metabolism (Kmono/Rate Pressure Product) by PET in Each Study Group. | Oxidative metabolism (Kmono/rate pressure product) by PET. | Baseline study visit | 
| 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. | Baseline study visit | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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magnetic resonance imaging, positron-emission tomography, echocardiography, myocardial blood flow, energy metabolism