Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition - Aim 3

This is a double-blind, randomized, two x two crossover (aprepitant vs placebo) during both initiation of Entresto, LCZ696, (50 mg dose) and at steady-state of Entresto (200 mg bid dose or the highest tolerated dose).

Inclusion Criteria: 1. Black and white men and women 2. Stable patients with a reduced ejection fraction (EF) 1. EF ≤55%, and 2. history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF) 3. stable clinical symptoms including no hospitalizations for the last three months, or one month if hospitalized only once for initial diagnosis of HF 4. who are not already taking LCZ696 3. treatment with a stable dose of an angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) and with a beta blocker (unless contraindicated or not tolerated) for at least four weeks 4. for patients with NYHA Class II or III HF and EF ≤35%, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or adverse reaction 5. For female subjects, the following conditions must be met: 1. postmenopausal status for at least one year 2. status post-surgical sterilization 3. or if childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β-HCG testing on every study day 6. Age 18 years of age or older Exclusion Criteria: 1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACEi, ARBs, or neutral endopeptidase inhibitor (NEPi), as well as known or suspected contraindications to the study drugs 2. History of angioedema 3. History of decompensated HF within the last 3 months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization) or one month if hospitalized only once for initial diagnosis of HF 4. History of heart transplant or on a transplant list or with left ventricular assistance device 5. Symptomatic hypotension and/or a systolic blood pressure (SBP)\