Physical Activity, Cardiac and Skeletal Muscle Energetics in Healthy Subjects and HFpEF Patients

All Participants:

• Women and men between the ages of 40 and 85 years, inclusive, at the Screening visit.
• Women of childbearing potential require a negative pregnancy test.
• Participants who are willing and able to comply with all scheduled visits, laboratory tests, lifestyle considerations, and other study procedures.
• Capable of giving signed informed consent, which includes willingness to be compliant with the requirements and restrictions listed in the informed consent document and in this protocol.

Healthy Participants Only :

• Healthy participants with no history of diabetes mellitus, or significant heart or vascular disease, including a history of heart failure, myocardial infarction, revascularization or positive exercise tolerance test for ischemia (if previously performed).
• BMI of 30.0 - 50.0 kg/m2, inclusive

Heart Failure Participants Only:

• Previous clinical diagnosis of heart failure with New York Heart Association (NYHA) Class II-IV symptoms at screening visit and present for at least 1 month.
• Symptom(s) of HF requiring treatment with diuretic(s) for at least 30 days prior to screening
• Left ventricular ejection fraction (EF) >=50% by echocardiography, MRI, CT or x-ray or nuclear ventriculography at screening visit or within prior 12 months.
• Patients with at least 1 of the following:
• HF hospitalization (defined as HF listed as the major reason for hospitalization and treatment with diuretics) or outpatient diuresis visit within 24 months prior to screening visit OR
• evidence of structural cardiac changes or elevated biomarkers. The structural changes are defined by at least 1 of the following echocardiography findings (any local measurement made during the screening epoch or within the 6 months prior to screening visit):
• Left Atrium (LA) enlargement defined by at least 1 of the following: LA width (diameter) ≥3.8 cm or LA length ≥5.0 cm or LA area ≥20 cm2 or LA volume ≥55 ml or LA volume index ≥29 ml/m2 ,
• Left Ventricular Hypertrophy (LVH) defined by septal thickness or posterior wall thickness ≥1.1 cm.
• The biomarker changes are defined as N terminal (NT)-proBNP >200 pg/ml for patients not in atrial fibrillation (AF) or >600 pg/ml for patients in AF on screening.
• Stable cardiovascular medical therapy for at least 30 days, defined as no addition or removal or major (>100%) dose change of prescribed medications for the treatment of cardiovascular disease such as, but not limited to: Renin-Angiotensin-Aldosterone System (RAAS) antagonists, beta-blockers, or calcium channel blockers for hypertension.
• At Visit 1 (Screen 1), BMI of 30.0 - 50.0 kg/m2, inclusive.

Exclusion Criteria:

All participants

Participants are excluded from the study if any of the following criteria apply:

• Age \< 40 years or > 85 years
• A history of myocardial infarction, stroke, or transient ischemic attack, within 6 months of Screen 1 (Visit 1);
• Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin); a subject is considered cured if there has been no evidence of cancer recurrence in the previous 5 years.
• Participants with any contraindication to MRI scanning or an anatomical or pathological abnormality that would either preclude or tend to confound the analysis of study data, including the following:
• History of severe claustrophobia impacting ability to perform MRI during the study
• Implanted metallic objects contraindicated in MRI such as (pre-existing cardiac pacemakers, cerebral clips) or indwelling metallic projectiles;
• Participants unable to fit within MRI scanner or follow instructions.
• Fasting serum triglycerides ≥500 mg/dL (5.6 mmol/L) on current medications
• Fasting LDL-C ≥190 mg/dL (4.9 mmol/L) on current medications

Prior/Concomitant Therapy:

• Use of prior/concomitant weight loss pharmacotherapy or weight loss surgery within the prior six months.

Healthy [Non-HFpEF] Participants Only:

In addition, Healthy Participants presenting with any of the following will not be included in the study:

• Screening supine 12 lead ECG demonstrating evidence of prior infarction or ischemia, significant arrhythmia or clinically significant conduction abnormalities.
• Uncontrolled hypertension, or those participants requiring greater than 2 blood pressure lowering medications.
• Screening Fasting glucose level of ≥126 mg/dL.
• History of diabetes mellitus
• Significant heart or vascular disease, including a history of heart failure, myocardial infarction, revascularization or positive exercise tolerance test for ischemia (if previously performed).
• Other medical or psychiatric condition that may increase the risk of study participation or, in the investigator's judgment, make the participant inappropriate for the study.

Heart Failure Participants Only:

• History of infiltrative cardiomyopathy or constrictive pericarditis, cor pulmonale, or significant pulmonary disease.
• Significant valvular abnormalities.
• History of clinical coronary artery disease (CAD) or significant epicardial coronary disease (>50% stenosis) in major coronary artery by x-ray or CT angiography unless (a) the patient underwent prior successful revascularization with percutaneous coronary angioplasty within the prior three years.
• Any condition other than HF which could limit the ability to perform a six minute walk test (6MWT) or CPET test (e.g., critical peripheral vascular disease, significant orthopedic or neurological conditions),
• Any diseases other than HF which are likely to significantly alter the patient's global perception of status or quality of life over a period of 6 months.
• Participants who have previously had a transplanted kidney, liver, or heart.
• At Screening, persistent severe, uncontrolled hypertension; for example: seated systolic blood pressure (SBP) ≥180 mm Hg and/or diastolic blood pressure (DBP) ≥105 mm Hg after ≥5 minute of seated rest, with a single repeat permitted to assess eligibility, if needed.
• At Screening, participants with an estimated glomerular filtration rate (eGFR) of ≤30 mL/min/1.73m2 using the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and serum creatinine (SCr).
• Patients taking combined glucagon-like peptide and gastric inhibitory polypeptide (GLP-1/GIP) receptor agonists at the time of the screening study visit.