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.