Severe skeletal wasting and catabolic weight loss are highly common among patients with heart failure with reduced ejection fraction (HFrEF). This prospective randomized controlled trial will compare changes in the muscle mass in the arms and the legs (appendicular lean mass) in patients with HFrEF randomized between 3 groups of no, low- or high-dose protein supplementation. The dietary protein supplementation will be Ensure(R) products manufactured by Abbott Nutrition. The Investigators hypothesize that skeletal muscle wasting in HFrEF is promoted by neurohumoral activation of catabolic metabolism (such as GDF-15 and ActRII pathways) and can be at least partially reversed by increased dietary protein intake. It is anticipated that this study will determine whether dietary protein supplementation helps to prevent muscle wasting and will advance understanding of the GDF-15 and ActRII muscle wasting pathways.

Inclusion Criteria:

1. Left ventricular ejection fraction (LVEF) ≤40%, New York Heart Association (NHYA) class II to IV symptoms or N-terminal pro B-natriuretic peptide (NT-proBNP) >300 pg/mL
2. Age 18 years to 100 years, inclusive
3. Receiving guideline-directed medical therapy (GDMT), unless contraindicated or not tolerated
4. Any of the following markers of severe HF within prior 12 months: i) Inotropic therapy; ii) 1 or more HF hospitalizations; iii) LVEF ≤25%; iv) Peak oxygen consumption (VO2) <50% predicted or ≤16 mL/kg/min; v) 6-minute walk distance <300 meters; vi) Unintentional weight loss >5% of bodyweight over the past year; vii) Moderate or severe muscle wasting on physical examination; viii) NT-proBNP ≥900 pg/mL

Exclusion Criteria:

1. Pregnancy, planning to become pregnant, or women of reproductive potential unwilling to complete pre-DXA urine pregnancy test before first DXA or randomization
2. History of left ventricular assist device (LVAD), heart transplantation, or estimated glomerular filtration rate (eGFR) <20 mL/min/1.73 m2
3. An identified clinical disorder associated with skeletal muscle weakness/wasting (e.g., muscular dystrophy, mitochondrial disorder, active cancer, modified Rankin score greater or equal to 4 post-stroke)
4. Milk allergy, protein allergy, lactose intolerance, and galactosemia
5. Weight ≥350 pounds and/or BMI ≥40 kg/m2
6. Initiation of obesity-dosed GLP-1 or GIP/GLP-1 agonist within 3 months prior to screening, or clinical intention to begin such an anti-obesity medication within the next 6 months.

Data sharing plans will be reviewed by the Tufts Health Sciences IRB and no identifiable participant data will be shared outside Tufts Medical Center. A data use agreement (DUA) will be completed between the PI and collaborating sites.

After primary and secondary analyses have been completed and the major findings for each Aim accepted for publication.

Due to the small sample size and single center location of the subjects, there remains a potential for deductive disclosure of subjects with unique clinical characteristics. Thus, the DUA will include language requiring: (1) a commitment to using the data only for research purposes and not to identify any individual participant; (2) a commitment to securing the data using appropriate computer technology; and (3) a commitment to destroying or returning the data after analyses are completed.