Mechanisms Underlying Hypotensive Response to ARB/NEP Inhibition – Aim 2

Inclusion Criteria:

Black and white men and women

Stable patients with a reduced ejection fraction (EF)

EF ≤40%, and
history of symptoms of New York Heart Association (NYHA) class I, II, or III heart failure (HF)
stable clinical symptoms including no hospitalizations for the last six months
who are not already taking LCZ696
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
for patients with NYHA Class II or III HF, treatment with a stable dose of an mineralocorticoid receptor (MR) antagonist for at least four weeks, unless not possible due to renal function or serum potassium.

For female subjects, the following conditions must be met:

postmenopausal status for at least one year, or
status post-surgical sterilization
or if of childbearing potential, utilization of barrier methods of birth control or an oral contraceptive and willingness to undergo urine β- human chorionic gonadotropin (HCG) testing on every study day

Exclusion Criteria:

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
History of angioedema
History of decompensated HF within the last three months (exacerbation of chronic HF manifested by signs and symptoms that required intravenous therapy or hospitalization)
History of heart transplant or on a transplant list or with left ventricular assistance device
Symptomatic hypotension and/or a systolic blood pressure (SBP)<100 mmHg at screening or <95 mmHg during the study
Serum potassium >5.2 mmol/L at screening or >5.4 mmol/L during the study

Impaired renal function (eGFR of <30mL/min/1.73 m2) as determined by the four-variable Modification of Diet in Renal Disease (MDRD) equation, where serum creatinine (Scr) is expressed in mg/dL and age in years:

eGFR (mL/min/1.73 m2)=175 • Scr-1.154 • age-0.203 • (1.212 if Black) • (0.742 if female)

Acute coronary syndrome, cardiac, carotid, or other major cardiovascular surgery, percutaneous coronary intervention, or carotid angioplasty within six months prior to screening
Coronary or carotid artery disease likely to require surgical or percutaneous intervention within six months of screening
History of serious neurologic disease such as cerebral hemorrhage, stroke, seizure, or transient ischemic attack
History of ventricular arrhythmia with syncopal episodes
Symptomatic bradycardia or second- or third-degree atrioventricular block without a pacemaker
Presence of hemodynamically significant mitral and/or aortic valve disease, except mitral regurgitation secondary to left ventricle (LV) dilatation
Presence of other hemodynamically significant obstructive lesions of the LV outflow tract, including aortic and subaortic stenosis
Type 1 diabetes
Poorly controlled type 2 diabetes mellitus (T2DM), defined as a HgbA1c >9%
In T2DM, dipeptidyl peptidase-4 inhibitor use for one month prior to enrollment will be excluded due to possible interaction with LCZ696
Hematocrit <35%
Breast feeding and pregnancy
History or presence of immunological or hematological disorders
History of malignancy not felt to be cured, except non-melanoma skin cancer
Diagnosis of asthma requiring use of inhaled beta agonist more than once a week
History of hypersensitivity reaction to contrast
Clinically significant gastrointestinal impairment that could interfere with drug absorption
History of pancreatitis or known pancreatic lesions
Impaired hepatic function [aspartate amino transaminase (AST) and/or alanine amino transaminase (ALT) >3.0 x upper limit of normal range]
Any underlying or acute disease requiring regular medication which could possibly pose a threat to the subject or make implementation of the protocol or interpretation of the study results difficult, such as arthritis treated with non-steroidal anti-inflammatory drugs
Treatment with chronic systemic glucocorticoid therapy within the last year
Treatment with lithium salts
History of alcohol or drug abuse
Treatment with any investigational drug in the one month preceding the study
Mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, and unlikelihood of completing the study