Effects of Sacubitril/Valsartan Therapy on Biomarkers, Myocardial Remodeling and Outcomes.

Inclusion Criteria:

Based on the USPI for sacubitril/valsartan, subjects eligible for inclusion in this study
must fulfill all of the following criteria at screening and baseline:

1. Written informed consent must be obtained before any assessment is performed.

2. Men and women ≥ 18 years of age.

3. LVEF ≤ 40% subjects who are candidates for on-label sacubitril/valsartan treatment per
standard of care.

4. New York Heart Association (NYHA) Functional class II-IV.

5. LVEF ≤40% via any local measurement within the past 6 months using echocardiography,
multi gated acquisition scan (MUGA), CT scanning, MRI or ventricular angiography
provided no subsequent study documenting an EF of >40%. If the EF measurement is
expressed as a value range, the average of the range endpoint values should be used as
the EF.

6. If a subject is on a loop diuretic, they must be on a stable dose for 2 weeks prior to
baseline.

Key Exclusion Criteria:

Subjects fulfilling any of the following criteria, at screening and prior to dispensing of
study drug, are not eligible for inclusion in this study. No additional exclusions may be
applied by the investigator, in order to ensure that the study population will be
representative of all eligible subjects/subjects.

1. History of hypersensitivity to any of the study drugs, including history of
hypersensitivity to drugs of similar chemical classes, or allergy to angiotensin
converting enzyme inhibitor (ACEIs), Angiotensin II Receptor Blockers (ARBs), or
Neutral endopeptidase (NEP) inhibitors as well as known or suspected contraindications
to the study drugs.

2. History of angioedema drug related or otherwise.

3. Requirement of treatment with either ACE inhibitor and/or ARB.

4. Subjects with a heart transplant or ventricular assistance device (VAD) or intent to
transplant (on transplant list) or implant a VAD.

5. Subjects with a cardio resynchronization therapy devices (CRT/CRT-D) implanted within
6 months of screening visit.

6. Subjects who are currently taking inotropic agents.

7. Current or prior treatment with sacubitril/valsartan.

8. Subjects taking medications prohibited by the protocol.

9. Subjects with diabetes mellitus who are taking aliskiren.

10. Use of other investigational drugs within 5 half-lives of enrollment, or within 30
days until the expected pharmacodynamic effect has returned to baseline, whichever is
longer.

11. Concomitant use of nesiritide.

12. Bile acid sequestering agents such as cholestyramine or colestipol are prohibited to
avoid interference with study drug absorption.

13. Any hospital admission/discharge related to heart failure within 2 weeks prior to
baseline.

14. The use of outpatient or inpatient i.v. diuretic therapy within 2 weeks prior to
baseline.

15. Enrollment in another clinical trial within 30 days of screening.

16. . Potassium > 5.2 mEq/L at screening.

17. History of malignancy of any organ system (other than localized basal cell carcinoma
of the skin), treated or untreated, within one year.