Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial
Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial
The enormous and rapidly growing burden of Heart Failure with Preserved Ejection Fraction
 (HFpEF) has led to a need to understand the pathogenesis and treatment options for this
 morbid disease. Recent research from the investigator's group and others have shown that
 pulmonary hypertension (PH) is highly prevalent in HFpEF, and right ventricular (RV)
 dysfunction is present in both early and advanced stages of HFpEF.

 These abnormalities in the RV and pulmonary vasculature are coupled with limitations in
 pulmonary vasodilation during exercise. There are no therapies directly targeted at the
 pulmonary vasculature that have been clearly shown to be effective in HFpEF. A recent study
 by Mayo Clinic Investigators has demonstrated pulmonary vasodilation with dobutamine (a beta
 2 agonist) in HFpEF. As an intravenous therapy, this is not feasible for outpatient use.

 In the proposed randomized, placebo-controlled double blinded trial, the investigators seek
 to evaluate whether the commonly used inhaled bronchodilator albuterol (a beta 2 agonist),
 administered through a high-efficiency nebulizer device that achieves true alveolar drug
 delivery, improves pulmonary vascular resistance (PVR) at rest and during exercise in
 patients with HFpEF as compared to placebo. This has the potential to lead to a simple cost
 effective intervention to improve symptoms in HFpEF, and potentially be tested in other World
 Health Organization (WHO) Pulmonary Hypertension groups. PVR is an excellent surrogate marker
 for pulmonary vasodilation and has been used in previous early trials of PH therapy.
Preliminary studies to support feasibility: Recent research from the investigator's group has
 shown that right ventricular (RV) dysfunction is present in a third of patients with HFpEF
 and the presence of pulmonary vascular disease and pulmonary hypertension (PH) is very high
 (related to both pulmonary venous hypertension as well as pulmonary vascular disease). Both
 of these have been associated with adverse outcomes and exercise intolerance but no therapy
 is currently available directly targeted at the pulmonary vasculature in HFpEF.

 The investigators recently demonstrated significant improvements in pulmonary vascular
 function with dobutamine (a β2 agonist) administered acutely in HFpEF. As an intravenous
 therapy, this is not suitable for chronic outpatient use. Hospitalized patients with heart
 failure often demonstrate symptomatic improvement with inhaled β2 agonist therapy, even in
 the absence of pulmonary disease, and animal studies have also shown improved resolution of
 pulmonary edema with albuterol. In the proposed randomized, double blinded placebo-controlled
 trial, the investigators seek to evaluate whether the commonly used inhaled bronchodilator
 albuterol, administered through a high-efficiency nebulizer device, improves pulmonary
 vascular function in patients with HFpEF-PH as compared to placebo. This has the potential to
 lead to a simple cost effective intervention to improve symptoms in HFpEF-PH, and potentially
 be tested in other WHO PH groups.

 In the absence of frank signs of congestive heart failure, patients with early HFpEF can only
 be reliably diagnosed by exercise right heart catheterization, which is routinely performed
 at Mayo Clinic as part of the evaluation of patients with unexplained dyspnea. The presence
 of elevated pulmonary capillary wedge pressures (PCWP) at rest (>15 mmHg) or with exercise
 (>25 mmHg); and elevated mean pulmonary artery pressures at rest (>25 mm Hg) and with
 exercise (>40 mmHg) has been used to invasively diagnose HFpEF with exercise pulmonary
 hypertension with a high degree of validity and reliability. Just as exercise stress unmasks
 abnormalities in left ventricular (LV) diastolic function in early stage HFpEF, the
 investigators have very recently shown that exercise stress reveals early abnormalities in
 pulmonary artery vascular function as compared to controls without HF that are not apparent
 from resting data alone.

 Using objective diagnoses of HFpEF and exercise induced PH, the investigators seek to
 evaluate the hemodynamic changes with exercise in pulmonary vascular resistance, peak cardiac
 output and subjective dyspnea before and after inhaled albuterol therapy for pulmonary
 vasodilation.

 Study design: This study will be performed in a randomized, double blind placebo-controlled
 fashion using inhaled albuterol or inhaled saline (prepared by research pharmacy)
 administered through a novel high-efficiency nebulizer in a 1:1 fashion. Patients will
 undergo right heart catheterization (RHC) with expired-gas analysis using high Fidelity
 micromanometer catheters at rest and with exercise, at baseline and following treatment with
 study drug, using a novel study design that the investigators have previously utilized and
 reported. Rest and exercise measurements will be repeated after receiving inhaled albuterol
 or control therapy.

 Patients referred to the cardiac catheterization laboratory for invasive exercise stress
 testing will be prospectively recruited. Standard RHC using high fidelity micromanometers
 (Millar Instruments) will be performed at rest and during supine exercise with simultaneous
 expired gas analysis (MedGraphics) as is our current practice. The protocol is rest-20 Watts
 exercise x 5 minutes, and then graded workload increases in 10-20 Watt increments (3 minute
 stages) to exhaustion. Hemodynamic, arterial and mixed venous blood gas and expired gas data
 are acquired at rest, during each exercise stage and at peak exercise. Venous blood samples
 will be obtained at rest and at peak exercise. Perceived symptoms of dyspnea and fatigue will
 be quantified using the Borg dyspnea and effort scores at each stage of exercise. Limited
 echocardiography will be performed by a cardiologist skilled in imaging focused on measures
 of RV morphology and function.

 After the initial exercise study and hemodynamics have returned to baseline, study drug
 (normal saline placebo or albuterol 2.5 mg) will be inhaled through a high efficiency
 nebulizer over 5 minutes. After a 10 minute observation period, resting hemodynamic and
 expired gas data will be acquired exactly as in the initial run. Subjects will then repeat
 the 20 Watt x 5 minutes exercise phase. Subjects will repeat exercise only at the 20 Watt
 stage, rather repeating the entire study. This is done to increase the feasibility and
 shorten the time of the case. The investigators have previously observed that the vast
 majority (>85%) of the elevation in cardiac filling pressures and reduction in venous oxygen
 content in people with HFpEF occurs at the low 20 Watt workload, so repeating exercise
 hemodynamic assessment at this load should be sufficient to detect any clinically meaningful
 treatment effect from albuterol.
Inclusion Criteria:

 -  Heart Failure with Preserved Ejection Fraction (HFpEF)

 -  Normal left ventricular ejection fraction (≥50%)

 -  Elevated Left Ventricular filling pressures at cardiac catheterization (defined as
 resting Pulmonary Capillary Wedge Pressure>15 mmHg and/or ≥25 mmHg during exercise).

 Exclusion Criteria:

 -  Prior albuterol therapy (within previous 48 hours)

 -  Current long acting inhaled beta agonist use

 -  Significant hypokalemia (<3meq/L)

 -  Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)

 -  High output heart failure

 -  Severe pulmonary disease

 -  Unstable coronary disease

 -  Constrictive pericarditis

 -  Restrictive cardiomyopathy

 -  Hypertrophic cardiomyopathy