| Eligibility |
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.
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