Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial
Phase: PHASE3
Conditions: Congestive Heart Failure, Heart Failure, Left-Sided, Left-Sided Heart Failure
Sponsor: Mayo Clinic

 
 
Inhaled Beta-adrenergic 
Agonists to Treat Pulmonary 
Vascular Disease in Heart 
Failure with preserved EF (BEAT 
HFpEF): A Randomized 
Controlled Trial 
 
NCT# 02885636 
 
July 21, 2016 

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Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure with 
preserved EF (BEAT HFpEF): A Randomized Controlled Trial 
 
 
 
Abstract:  
Heart failure (HF) is the most common cause of pulmonary hypertension (PH, WHO Group 2) 
(1). Approximately half of patients with HF have preserved ejection fraction (HFpEF) (2); PH is common 
in this cohort and is clearly associated with increased mortality (3)(4)(5)(6). While early stages of 
HFpEF are characterized by purely passive PH, recent studies have shown that the majority of patients 
referred for invasive assessment display significant pulmonary vascular disease (HFpEF-PH) manifest 
by elevation in pulmonary vascular resistance and decreases in pulmonary artery compliance (7)(8).  
Patients with HFpEF-PH frequently display right ventricular (RV) dysfunction, which is associated with 
even worse outcome, independent of the severity of PH (9).  We have recently shown that the RV in 
HFpEF displays greater afterload-dependence as compared to healthy controls (9), suggesting that 
there may be greater opportunity to improve hemodynamics and functional capacity with pulmonary 
vasodilators in this population. We have also shown that even in the earliest stages of HFpEF, there is 
abnormal pulmonary vasodilation associated with impaired RV reserve.(10)  This suggests potential for 
patients with HFpEF to benefit from pulmonary vasodilators, but no approved therapies are available 
directly targeting the pulmonary vasculature in HFpEF. 
 
Our group has recently shown that the pulmonary vasculature in patients with HFpEF-PH is very 
favorably responsive to beta-adrenergic stimulation from intravenous dobutamine (11). Compared to 
controls, dobutamine produced significantly greater reductions in pulmonary artery (PA) pressure, 
resistance and more improvement in PA compliance in subjects with HFpEF. This observation serves 
as the guiding hypothesis for the proposed study: that acute treatment with an inhaled beta-agonist 
(albuterol) can improve pulmonary vascular function at rest and during exercise in patients with HFpEF-
PVD.  Demonstration of such an acute effect from a novel inhaled therapy would represent a major step 
forward in the potential treatment of a large population of patients with pulmonary vascular disease for 
whom there is currently no effective pharmacotherapy. 
 
 
 
 
 
Principal Investigator: 
 
Barry A. Borlaug, MD  
 
Co-Investigators  
 
Yogesh N. V. Reddy, MD and Masaru Obokata, MD 
 
 
 
 

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A. Rationale: In contrast to heart failure (HF) with reduced EF, there is no effective treatment for HF 
with preserved EF (HFpEF).  Pulmonary hypertension (PH) is highly prevalent in HFpEF and is 
associated with right ventricular (RV) dysfunction and increased mortality, particularly when both the 
former and latter are present.  Recently, we have also shown that there is depressed pulmonary artery 
(PA) vasodilation during exercise, even when resting indices of function are normal. This is associated 
with impaired RV reserve and reduced exercise capacity. Dobutamine, a nonselective β-agonist, 
improves PA vascular function at rest in HFpEF, but is limited by the fact that it is an intravenous 
therapy that is not feasible for chronic ambulatory use. Albuterol is an inhaled β-agonist routinely used 
to treat reactive airway diseases that could provide an alternate way of improving PA vascular function 
in patients with HFpEF-PH.   
B. Hypothesis:  Acute inhaled albuterol will improve PA vascular function at rest and during exercise in 
subjects with HFpEF-PH. 
 
C. Innovation:  
• 
The hypothesis proposed is based on our own data and has not been entertained by other 
groups and β-agonists (albuterol) have never been suggested to treat HFpEF 
• 
The use of exercise hemodynamics to measure an intervention’s effect is highly novel while also 
being clinically meaningful.  Very few centers in the world could carry out this study. 
• 
This application is based upon a highly innovative hypothesis that HFpEF is caused by dynamic 
abnormalities in cardiac reserve rather than simply resting diastolic dysfunction. 
• 
The concept of a therapy that can be given prophylactically before activity in HFpEF is highly 
innovative. 
• 
The commonly used bronchodilator albuterol has never been tested as a pulmonary vasodilator. 
If effective this could lead to further studies in other forms of pulmonary hypertension 
D. Significance:   
• 
HFpEF currently afflicts 2-3 million Americans, and with the aging population the prevalence is 
growing by 1% per year.  This makes identification of effective treatments a major unmet public 
health need that will change our practice. 
• 
Mayo is already a leader in the invasive characterization of HF, and publication of the results of 
these studies will further enhance our international reputation as a center of excellence.   
• 
By conducting trials of novel interventions like albuterol in HFpEF, this trial will enhance referrals 
of patients with unexplained dyspnea and exercise intolerance to Mayo. 
• 
Identification of a beneficial effect of albuterol on hemodynamics would provide critical 
preliminary data to support a larger Mayo-centered, NIH-sponsored clinical trial of chronic 
albuterol therapy in HFpEF. 
E. Brief Synopsis of Methods:  
1) Enroll subjects with normal EF referred to the cath lab for evaluation of dyspnea. 
2) Measure resting and exercise hemodynamics with expired gas analysis as per clinical practice. 
3) After exercise, in a randomized, double-blinded fashion, administer inhaled albuterol or placebo 
(prepared by research pharmacy). 
4) Repeat rest-exercise hemodynamics/expired gas analysis exactly as above. 
5) Compare resting and exercise hemodynamic response after albuterol or placebo relative to the 
initial assessment (analysis of covariance, ANCOVA).  
6) Perform simultaneous echo with measurement of RV function using tissue Doppler 
echocardiography and PA flow using pulsed wave Doppler of the RV outflow tract during rest 
and exercise phases. 

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F. Preliminary studies to support feasibility: The enormous and rapidly growing burden of HFpEF 
has led to a need to better understand the pathogenesis and treatment options for this morbid disease. 
Recent research from our group has shown that 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) ((12)) ((5)). 
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 ((9)).  
We recently demonstrated significant improvements in pulmonary vascular function with 
dobutamine (a β2 agonist) administered acutely in HFpEF (11). 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 (13), 
(14,15). In the proposed randomized, placebo-controlled trial, we 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 (16). Just as exercise stress unmasks abnormalities in LV diastolic function in early stage 
HFpEF, we have very recently shown that exercise stress reveals early abnormalities in PA vascular 
function as compared to controls without HF that are not apparent from resting data alone.(10)   
Using objective diagnoses of HFpEF and exercise induced PH, we 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.  
 
G. 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 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 we have previously utilized and 
reported (17). 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 right heart catheterization 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 10-20W 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 (MO) focussed 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 

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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. We 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 (16), so repeating exercise hemodynamic assessment at 
this load should be sufficient to detect any clinically meaningful treatment effect from albuterol.   
Blood tests: No additional blood tests will be collected beyond those needed for clinical use in the right 
heart catheterization. 
Data collected: This will be a randomized double-blind trial.  A web data base will be created (Redcap) 
using dual data entry from the paper case report forms. All hemodynamic data will be assessed at end 
expiration using standard methods by the PI to minimize interobserver variability.  Data will be supplied 
for analysis as an SAS data base. The specific hemodynamic and expired gas data along with blood 
tests obtained are itemized in Appendix I.  
Primary Endpoint:  The primary endpoint will be the PVR at 20 Watts exercise after study drug relative 
to the PVR at 20 Watts exercise in the initial assessment prior to study drug. 
Secondary Endpoints:  Secondary endpoints will be changes in resting PVR after study drug as well 
as rest and exercise changes in PA compliance, right atrial pressure, pulmonary artery pressure, 
PCWP, cardiac output, RV systolic and diastolic function, PA input impedance VO2, Ve/VCO2 slope and 
Borg effort/dyspnea scores.   
We will also perform a prespecified tertiary analysis of Beta blocker+ vs Beta blocker- subjects enrolled 
to see if there is any difference in treatment effect. 
Inclusion Criteria: HFpEF is defined by clinical symptoms of dyspnea and fatigue, normal left 
ventricular ejection fraction (≥50%), and elevated LV filling pressures at cardiac catheterization (defined 
as resting PCWP>15 mmHg and/or PCWP≥25 mmHg during exercise). 
Exclusion Criteria: Prior albuterol therapy (within previous 48 hours), current long acting inhaled beta 
agonist use, significant hypokalemia (<3meq/L), other “non-HFpEF” specific causes of heart failure 
such as significant valvular disease (>moderate left-sided regurgitation, >mild stenosis), high output 
heart failure, severe pulmonary disease, unstable coronary disease, constrictive pericarditis, or 
infiltrative, restrictive, or hypertrophic cardiomyopathies. Patients who are pregnant or lactating will also 
be excluded. 
We will include patients on chronic beta blocker (BB) therapy in the study for the following reasons (1) 
they are commonly prescribed in HFpEF, so to restrict to BB naive patients will limit our ability to 
generalize the findings, (2) the requirement would limit the pool of patients who might be eligible for the 
study, (3) chronically, BBs restore beta-adrenergic responsiveness in heart failure, so they are unlikely 
to significantly attenuate albuterol’s effect in the heart and pulmonary vasculature  
Study drug preparation and considerations: Medical grade albuterol nebulization solution will be 
obtained by research pharmacy from the Mayo Clinic pharmacy at a dose of 2.5 mg for nebulization 
(current FDA approved dose for bronchodilation). Placebo (normal saline) will also be prepared by 
research pharmacy for nebulization at identical weight-based rate.  The randomization scheme will be 
generated by the cath lab statistician, Ryan Lennon and entered into a computer program.   
H. Statistical analysis and power considerations:  
We will enroll 30 patients (15 in each arm) over a 1 year period. In our previous study, PVR was 
improved by 0.8 with dobutamine in subjects with HFpEF. Assuming a standard deviation of 0.5 WU in 
exercise PVR based upon our prior data, this sample size will provide 98% power (alpha=0.05) to 
detect a drop in exercise pulmonary vascular resistance of this magnitude or greater with albuterol as 
compared to inhaled placebo.  
 
The effect of albuterol relative to placebo on primary and secondary endpoints will be evaluated by 
analysis of covariance (ANCOVA) taking into account rest/exercise values prior to study drug and 
following albuterol or placebo. 

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Consenting subjects who do not meet the diagnostic criteria for HFpEF at catheterization (resting 
PCWP>15 mmHg and/or PCWP≥25 mmHg during exercise) will be considered screen failures and will 
not receive study drug. Given that we currently perform > 250 exercise right heart catheterizations per 
year at the Mayo clinic and have successfully completed similar acute hemodynamic studies over this 
time frame, we plan to reach the target of 30 enrolled HFpEF patients within 12 months. 
 
I.  Human studies issues:   
Informed consent will be obtained from each participant prior to coming to the catheterization laboratory. 
Albuterol is currently FDA approved at the proposed study drug dose of 2.5 mg through nebulization for 
treatment of obstructive lung disease. The medication is well tolerated overall and has been used in 
both young and old patients alike with lung disease with minimal side effects and excellent tolerability. 
Previous studies using albuterol in much sicker HF patients with decompensation and reduced ejection 
fraction as well as in critically ill patients have failed to demonstrate harm from the standpoint of 
tachyarrhythmias or other untoward effects (18-20). Patients with a normal EF and HFpEF are in 
general less acutely ill than these previously studied patients and are commonly treated with these 
agents in the presence of coexisting lung disease (which is very common in HFpEF).  
Side effects of albuterol are minimal and related to benign palpitations, tremors and anxiety. At higher 
doses of 10-20 mg, transient hypokalemia can occur through transcellular shift but this is not seen at 
the doses used in this trial. Patients with significant baseline hypokalemia will also be excluded by 
study design. Dobutamine and isoproterenol are similar β-agonists that are currently given 
intravenously in the cath lab as part of routine clinical practice without untoward significant untoward 
effects.(21,22) With direct pulmonary delivery, systemic side effects from albuterol are expected to be 
much less likely than would be observed with parenteral use of these IV active β-agonists. 
 
Patients will be monitored in the recovery area typically for up to two hours after their procedure to 
remove vascular sheaths. Patients will be monitored using continuous telemetry, heart rate and 
oximetry monitoring. Blood pressure will be monitored as per standard of care. This will allow post 
procedure observation in a monitored setting to ensure no side effects occur during peak drug 
concentration.  
J. Budget 
 
This study will be done in patients already undergoing cardiac catheterization and exercise 
hemodynamic study.  There will be no additional cost to the patient.  The only research charges will be 
for albuterol/placebo and for preparation and storage in research pharmacy, and for two additional 
arterial blood gases obtained during the subsequent rest and exercise phases after study drug. 
 
   
K. References: 
1. 
Fang JC, DeMarco T, Givertz MM, et al. World Health Organization Pulmonary Hypertension 
group 2: pulmonary hypertension due to left heart disease in the adult--a summary statement 
from the Pulmonary Hypertension Council of the International Society for Heart and Lung 
Transplantation. J Heart Lung Transplant 2012;31:913-33. 
2. 
Borlaug BA, Paulus WJ. Heart failure with preserved ejection fraction: pathophysiology, 
diagnosis, and treatment. Eur Heart J 2011;32:670-9. 
3. 
Kjaergaard J, Akkan D, Iversen KK, et al. Prognostic importance of pulmonary hypertension in 
patients with heart failure. Am J Cardiol 2007;99:1146-50. 
4. 
Lam CS, Borlaug BA, Kane GC, Enders FT, Rodeheffer RJ, Redfield MM. Age-associated 
increases in pulmonary artery systolic pressure in the general population. Circulation 
2009;119:2663-70. 
5. 
Lam CS, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary 
hypertension in heart failure with preserved ejection fraction: a community-based study. J Am 
Coll Cardiol 2009;53:1119-26. 

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6. 
Leung CC, Moondra V, Catherwood E, Andrus BW. Prevalence and risk factors of pulmonary 
hypertension in patients with elevated pulmonary venous pressure and preserved ejection 
fraction. Am J Cardiol 2010;106:284-6. 
7. 
Schwartzenberg S, Redfield MM, From AM, Sorajja P, Nishimura RA, Borlaug BA. Effects of 
vasodilation in heart failure with preserved or reduced ejection fraction implications of distinct 
pathophysiologies on response to therapy. J Am Coll Cardiol 2012;59:442-51. 
8. 
Guazzi M, Borlaug BA. Pulmonary hypertension due to left heart disease. Circulation 
2012;126:975-90. 
9. 
Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart 
failure with preserved ejection fraction. Eur Heart J 2014;35:3452-62. 
10. 
Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery 
coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J. 2016. 
11. 
Andersen MJ, Hwang SJ, Kane GC, et al. Enhanced pulmonary vasodilator reserve and 
abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection 
fraction. Circ Heart Fail 2015;8:542-50. 
12. 
Mohammed SF, Hussain I, AbouEzzeddine OF, et al. Right ventricular function in heart failure 
with preserved ejection fraction: a community-based study. Circulation 2014;130:2310-20. 
13. 
Matthay MA, Folkesson HG, Clerici C. Lung epithelial fluid transport and the resolution of 
pulmonary edema. Physiol Rev 2002;82:569-600. 
14. 
Frank JA, Wang Y, Osorio O, Matthay MA. Beta-adrenergic agonist therapy accelerates the 
resolution of hydrostatic pulmonary edema in sheep and rats. J Appl Physiol (1985) 
2000;89:1255-65. 
15. 
Licker M, Tschopp JM, Robert J, Frey JG, Diaper J, Ellenberger C. Aerosolized salbutamol 
accelerates the resolution of pulmonary edema after lung resection. Chest 2008;133:845-52. 
16. 
Borlaug BA, Nishimura RA, Sorajja P, Lam CS, Redfield MM. Exercise hemodynamics enhance 
diagnosis of early heart failure with preserved ejection fraction. Circ Heart Fail 2010;3:588-95. 
17. 
Borlaug BA, Koepp KE, Melenovsky V. Sodium Nitrite Improves Exercise Hemodynamics and 
Ventricular Performance in Heart Failure With Preserved Ejection Fraction. J Am Coll Cardiol 
2015;66:1672-82. 
18. 
Slutsky R. Hemodynamic effects of inhaled terbutaline in congestive heart failure patients 
without lung disease: beneficial cardiotonic and vasodilator beta-agonist properties evaluated by 
ventricular catheterization and radionuclide angiography. Am Heart J 1981;101:556-60. 
19. 
Uren NG, Davies SW, Jordan SL, Lipkin DP. Inhaled bronchodilators increase maximum oxygen 
consumption in chronic left ventricular failure. Eur Heart J 1993;14:744-50. 
20. 
Khorfan FM, Smith P, Watt S, Barber KR. Effects of nebulized bronchodilator therapy on heart 
rate and arrhythmias in critically ill adult patients. Chest 2011;140:1466-72. 
21. 
Andersen MJ, Hwang SJ, Kane GC, et al. Enhanced pulmonary vasodilator reserve and 
abnormal right ventricular: pulmonary artery coupling in heart failure with preserved ejection 
fraction. Circ Heart Fail. 2015;8:542-50. 
22. 
Prasad M, Geske JB, Sorajja P, et al. Hemodynamic changes in systolic and diastolic function 
during isoproterenol challenge predicts symptomatic response to myectomy in hypertrophic 
cardiomyopathy with labile obstruction. Catheter Cardiovasc Interv. 2016. 
 
 
 
 
 
 
 
 

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Appendix I: Data Obtained at baseline rest, baseline exercise, post study drug rest, and post 
study drug exercise stages 
 
Heart rate 
Systemic blood pressure (systolic, diastolic mean) 
Right atrial pressure 
Pulmonary arterial pressure (systolic, diastolic, mean) 
Pulmonary capillary wedge pressure (mean, V wave) 
Cardiac output (direct Fick method) 
Stroke volume 
LV and RV stroke work index 
Transpulmonary gradient 
Pulmonary and Systemic Vascular resistances 
Oxygen consumption  
Carbon dioxide production 
Respiratory exchange ratio 
Minute ventilation, tidal volume, respiratory rate 
Ventilatory efficiency (Ve/VCO2 slope) 
Borg perceived effort (6-20 scale) and dyspnea (0-10) scores 
Arterial blood gas and saturation to determine O2 content 
Mixed venous blood gas and saturation to determine O2 content 
Echo derived RV lateral annular tissue Doppler velocity during systole (s’) 
Echo derived RV lateral annular tissue Doppler velocity during diastole (e’) 
Echo derived RV outflow tract pulse wave Doppler profile