Influences of Angiotensin-neprilysin Inhibition on Sympathetic Activity in Heart Failure

Inclusion Criteria: 1. Women or men at the age ≥ 18 years, ≤ 80 years and able to give written informed consent 2. Heart failure NYHA class II-III 3. Ejection fraction of 40 % or less 4. Stable dose of an ACE inhibitor or ARB over the last 4 weeks (A 2-day ACE inhibitor washout is scheduled before run-in; see Figure 3 on page 29.) 5. Stable dose of a beta-blocker over the last 4 weeks unless contraindicated or not tolerated 6. Patient has to be in sinus rhythm 7. Patients capable of understanding the investigational nature, potential risks and benefits of the clinical trial 8. Women without childbearing potential defined by: * at least 6 weeks after surgical sterilization by bilateral tubal ligation or bilateral oophorectomy or * hysterectomy or uterine agenesis or * ≥ 50 years and in postmenopausal state ≥ 1 year or * \< 50 years and in postmenopausal state ≥ 1 year with urine FSH \> 40 IU/l and urine estrogen \< 30 ng/l or a negative estrogen test OR Women of childbearing potential with a negative urine ß-HCG pregnancy test at screening who agree to meet one of the following criteria from the time of screening, during the study and for a period of 7 days following the last administration of study medication: * correct use of at least an acceptable effective contraceptive measure. The following are deemed acceptable in this study: hormonal contraceptives (combined oral contraceptives and estrogen-free pills with desogestrel, implants, transdermal patches, hormonal vaginal devices or injections with prolonged release), intrauterine device (IUS)) * true abstinence (periodic abstinence and withdrawal are not acceptable methods of contraception) * sexual relationship only with female partners and/or sterile male partners OR Male 9. Signed written informed consent and willingness to comply with treatment and follow- up procedures. Exclusion Criteria: 1. History of hypersensitivity or allergy to any of the study drugs, drugs of similar chemical classes, ACE inhibitors (ACE-Is), ARBs, or neprilysin inhibitors, as well as known or suspected contraindications to the study drugs 2. History of angioedema 3. Recent acute decompensated heart failure within 2 months before screening 4. Symptomatic hypotension and/or office systolic BP \<110 mmHg at screening measured according to the recommendations of the European Society of Hypertension 5. Combined intake of an ACE inhibitor and ARB over the last 4 weeks 6. Estimated glomerular filtration rate (eGFR) \<30 mL/min/1.73 m² 7. Concomitant medication with Aliskiren in patients with Diabetes or patients with eGFR \< 60 mL/min/1.73 m² 8. Serum potassium \>5.2 mmol/L at Visit 1 (screening) 9. Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid, or other major cardiovascular surgery, PCI, or carotid angioplasty within the 3 months before screening 10. History of heart transplant or on a transplant list or with LV assistance device 11. History of severe pulmonary disease 12. Documented untreated ventricular arrhythmia with syncopal episodes within the 3 months prior to Visit 1 13. Presence of hemodynamically significant mitral and/or aortic valve disease/ left ventricular outflow tract obstruction, except mitral regurgitation secondary to LV dilatation 14. Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs 15. Evidence of hepatic disease as determined by any one of the following: aspartate aminotransferase or alanine aminotransferase values exceeding 2× upper limit of normal at Visit 1, history of hepatic encephalopathy, history of esophageal varices, or history of porto-caval shunt 16. Contraindications precluding microneurography measurements, such as relevant peripheral neuropathy as judged by the investigator 17. Pregnancy or lactation period 18. Current participation in any other clinical trial or participation in another clinical trial within 30 days before screening 19. Known or suspected hypersensitivity to any of the active substances or any excipients of the investigational medicinal products 20. Vulnerable subjects (i.e. persons under any administrative or legal supervision or persons kept in detention)