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

Inclusion Criteria:

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.