Understanding physical activity and heart function in healthy individuals and those with heart failure

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.