Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Study Overview
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Brief Summary
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The global objective of this study is to determine the mechanisms of exercise intolerance and dyspnea on exertion (DOE) in patients with HFpEF and based on this pathophysiology, test whether specific exercise training programs (whole body vs single leg) will result in improved exercise tolerance.

Detailed Description
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This will be a randomized, non-blinded prospective intervention testing the effects of two types of exercise training, whole body and isolated single leg, on HFpEF patients with either central or peripheral limitations to exercise training. Subjects will undergo baseline maximal exercise testing and invasive right heart catheterization to define exercise tolerance and pulmonary and cardiac pressures during exercise. Based on the results of baseline testing, subjects will be divided into either centrally limited, defined as excessive rise in pulmonary capillary wedge pressure more than 25 mmHg that decreases after administration of sub-lingual nitroglycerin resulting in improved exercise tolerance, or peripherally limited, defined as no improvement in exercise tolerance despite reduction in pulmonary capillary wedge pressure after sublingual nitroglycerin. After baseline testing, subjects will be randomized to either whole body cycle exercise supplemented with sublingual nitroglycerin to improve training responsiveness or isolated single leg exercise training for 4 months. After 4 months, subjects will repeat maximal exercise testing and invasive right heart catheterization to assess responses to 4 months of exercise training.

Official Title
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Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

Conditions
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Heart Failure, Diastolic

Intervention / Treatment
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* Behavioral: Exercise training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: signs and symptoms of heart failure an ejection fraction > 0.50 objective evidence of diastolic dysfunction Exclusion Criteria: age < 60 years BMI > 50 kg/m2 PDE5 inhibitor use Severe valvular disease Severe COPD CKD 4 or higher Contra-indication to MRI.

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 90 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Factorial Assignment
Interventional Model Description: HFpEF patients with either central or peripheral limitations to exercise will be randomly assigned to either whole body or isolated single leg exercise.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Central HFpEF whole body exercise<br>HFpEF patients who have a central limitation as the cause of the exercise intolerance randomized to whole body cycle training. | Behavioral: Exercise training<br>* Exercise training, either whole body or isolated single leg<br>|
| Experimental: Central HFpEF isolated single leg exercise<br>HFpEF patients who have a central limitation as the cause of the exercise intolerance randomized to isolated single leg training. | Behavioral: Exercise training<br>* Exercise training, either whole body or isolated single leg<br>|
| Experimental: Peripheral HFpEF whole body exercise<br>HFpEF patients who have a peripheral limitation as the cause of the exercise intolerance randomized to whole body cycle training. | Behavioral: Exercise training<br>* Exercise training, either whole body or isolated single leg<br>|
| Experimental: Peripheral HFpEF isolated single leg exercise<br>HFpEF patients who have a peripheral limitation as the cause of the exercise intolerance randomized to isolated single leg training. | Behavioral: Exercise training<br>* Exercise training, either whole body or isolated single leg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Aerobic fitness | Change in peak VO2 after exercise training | 4 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Cardiopulmonary hemodynamics | Change in exercise pulmonary capillary wedge pressure | 4 months | 
| Sympathetic activity | Change in muscle sympathetic activity | 4 months | 
| Leg blood flow | Change in leg blood flow assessed by Doppler velocities in femoral artery | 4 months | 
| Cardiac fibrosis | Change in T1 mapping times by cardiac MRI | 4 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Exercise, Hemodynamics,, Heart failure