The goal of this clinical trial is to learn if therapy with activin ligand-trap biological therapy (an investigational drug) combined with exercise training can improve exercise capacity and cognitive function in heart failure with preserved ejection fraction (HFpEF). The main questions it aims to answer are:

• Does activin-ligand trap biological therapy improve exercise capacity as measured by change in peak oxygen uptake (peak VO2) from baseline to week 12?
• Does activin-ligand trap biological therapy improve cognitive function as assessed by the NIH-Toolbox Cognition Battery (NIHTB-CB) composite score and Rey Auditory Verbal Learning Test (RAVLT) from baseline to week 12?

Researchers will compare activin-ligand trap biological therapy to a placebo (a look-alike substance that contains no drug) to see if activin-ligand trap therapy works to improve exercise capacity and cognitive function in patients with HFpEF.

A double-blind, prospective, phase 2 randomized, placebo-controlled 24-week clinical trial to assess exercise tolerance after activin-ligand trap biological therapy compared to placebo in HFpEF patients with a primary endpoint of change in peak VO2.

Forty-eight participants with HFpEF who are overweight or obese will be recruited from the Cardiopulmonary Exercise Testing (CPET) Laboratory and will have a recent or scheduled clinical care CPET. These measurements will serve as baseline measures. After undergoing other baseline measurements such as actigraphy, blood studies, DEXA scan, Kansas City Cardiomyopathy Questionnaire (KCCQ), NIHTB-CB, and RAVLT, participants will be randomized (1:1) to either activin-ligand trap biological therapy combined with physical activity (n=24) or placebo combined with physical activity (n=24). Randomization will be stratified by sex and will be performed in permutated blocks of 4 to assure balanced group sizes. In order to allocate without bias and in a manner blinded to both participants and investigators, we will use random number generation at the time of randomization. After 12 weeks, patients will return for a new CPET, physical exam, urine and blood test, echocardiogram, electrocardiogram, DEXA scan, actigraphy, assessment of NYHA class, NIHTB-CB, RAVLT, KCCQ, six-minute walk test, handgrip test, and adverse events assessment. After these assessments, patients will undergo crossover at week 12 and will receive either the activin-ligand trap biological therapy combined with physical activity (n=24) or the placebo combined with physical activity (n=24) for an additional 12 weeks. At week 24, patients will return to have a repeat of the same tests that were performed at week 12.

Inclusion Criteria:

1. Adult ≥ 40 years of age;

2. Body mass index ≥ 27 kg/m2;

3. Left ventricular ejection fraction (LVEF) ≥ 0.50 with NYHA II-III;

4. Established diagnosis of HFpEF based on medical history supported by at least one of the following 5 criteria (i through v, below)

   i. Documented hospitalization with HFpEF as a primary cause or other urgent outpatient visit for acute HFpEF (as primary cause) at which IV loop diuretic was provided as treatment (≥ 1 month prior to screening);

   ii. Increased left atrial (LA) size: AP dimension: ≥ 4.0 in men, > 3.8 in women; or LA length ≥ 5.0 cm or LA volume ≥ 55 mL or LA volume index≥ 29 mL/m2;

   iii. PCWP at rest > 15 mmHg (or LVEDP ≥ 18 mmHg) or ≥ 25 mmHg with exercise (or PCWP/CO ≥ 2.0 mmHg/L/min with exercise);

   iv. Either of the following at rest by Doppler and Tissue Dopper: a) for patients in sinus rhythm: E/e' ratio ≥ 15 at septal annulus, or E/e' ratio ≥ 13 at lateral annulus, or average E/e' ratio ≥ 14; for patients in atrial fibrillation E/e' ≥ 11 at the septal annulus;

   v. Elevated NT-proBNP ≥ 125 pg/mL (≥ 250 with chronic atrial fibrillation).

5. Achievement of a respiratory exchange ratio (RER) at baseline CPET of ≥ 1.05 to ensure maximum volitional effort was provided;

6. Ambulatory (not wheelchair/scooter-dependent) and able to perform CPET/6MWT/Chair stand evaluations;

7. Stable dose of medications (defined as no new medication or change in existing dose of medication ≥ 50%) for at least 30 days prior to screening.

Exclusion Criteria:

1. Conditions anticipated to independently impact exercise capacity or clinical stability during the trial period

   1. Current or recent (within 30 days) acute decompensated HF requiring intravenous diuretics or hospitalization;
   2. Initiation of treatment with GLP-1 receptor agonist or SGLT2 inhibitor within 60 days of screening;
   3. Planned cardiac surgery or catheter intervention during the period of trial participation;
   4. Entry within 30 days of screening or plans to enter a weight loss program and/or cardiac rehabilitation or initiate any new exercise program during the study.

2. Primary cardiomyopathy (e.g., constrictive, restrictive, infiltrative, toxic, hypertrophic, congenital), LVEF < 40% within the last 3 years, or active myocarditis;

3. Lactating, pregnant, or planning to become pregnant;

4. Non-cardiac organ system dysfunction or sufficient severity to predominate as the source of exercise intolerance in addition to the following specific criteria: pulmonary disease with chronic home daytime supplemental O2 dependence, severe anemia with hemoglobin < 9 g/dL or chronic kidney disease (CKD) with estimated GFR < 30 mL/min/1.73m2 based on the CKD-EPI equation.