Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial

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