Activin-Ligand TrapEXercise and Activin Inhibition to Modulate InflammatioN Effects on Heart Failure and Cognition (EXAMINE-HFC)

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.