Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction

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.

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.

HFpEF patients with either central or peripheral limitations to exercise will be randomly assigned to either whole body or isolated single leg exercise.

HFpEF patients who have a central limitation as the cause of the exercise intolerance randomized to whole body cycle training.

HFpEF patients who have a central limitation as the cause of the exercise intolerance randomized to isolated single leg training.

HFpEF patients who have a peripheral limitation as the cause of the exercise intolerance randomized to whole body cycle training.

HFpEF patients who have a peripheral limitation as the cause of the exercise intolerance randomized to isolated single leg training.

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.