The purpose of this research is to see if the drug rapamycin will improve the heart's ability to pump by improving your oxygen consumption.

This will be a pilot, proof-of-concept study. Patients 60 years or older with invasively proven HFpEF or have definite HFpEF as determined by the 2 established scores and frailty (positive screen for computable phenotype), will be approached for enrollment. Subjects meeting screening criteria following written informed consent will be randomized to receive rapamycin or matching placebo (study drug). Efficacy outcomes will be measured at baseline and at 6 months. Safety will be assessed by in person or remote video monitoring weekly for 1 month, then monthly for 5 months till the end of the study. We will also measure trough rapamycin levels (≤4ng/mL) twice-a-month for the first month and then monthly for 5 months.

Inclusion Criteria:

• Age ≥60 years
• Diagnosis of HFpEF by either H2FEPF score of 6-9 or HFA-PEFF score of 5-6, or invasively confirmed diagnosis of HFpEF (resting pulmonary capillary wedge pressure ≥15mmHg or ≥25mmHg with exercise).
• Diagnosis of computable phenotype of frailty rests on screening questions about ability to climb two flights of stairs, activities of daily living, living environment, wearing of dentures/hearing aids, and whether the patient uses assistive devices.

Exclusion Criteria:

• Reduced ejection fraction (≤50%) with or without prior history of myocardial infarction
• Acute coronary syndrome <3 months
• Uncontrolled diabetes mellitus (HbA1C>8)
• Uncontrolled hypertension (>160/100mmHg, despite 3 antihypertensive medications)
• Nephrotic syndrome or eGFR <30mL/min/1.73m2
• Cirrhosis
• Hepatitis B/C positive
• Elevated lived enzymes (AST/ALT>3ULN
• Prior malignancy other than basal cell carcinoma
• History of ongoing, chronic or recurrent infectious disease
• Suspected/proven immunocompromised state
• Uncontrolled hyperlipidemia (fasting TG >400 mg/dL (>4.5 mmol/L) or total cholesterol >300 mg/dL (>7.8 mmol/L) despite maximum lipid lowering therapy
• Class IV HF symptoms