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Background: Heart failure with reduced ejection fraction is associated with potentially deleterious imbalance of the cardiac autonomic nervous system. Sacubitril/valsartan (angiotensin receptor-neprilysin inhibitor [ARNI]) reduces cardiovascular mortality and hospitalization for heart failure with reduced ejection fraction. Whether ARNI affects the cardiac autonomic nervous system has not been studied., Methods and Results: This investigator-initiated, prospective, single-center cohort study compared heart rate (HR) variability, HR, deceleration capacity, and periodic repolarization dynamics as noninvasive measures of the cardiac autonomic nervous system before and after initiation of ARNI therapy. Patients underwent standardized 12-lead Holter-ECG, echocardiography and laboratory testing before and 3 months after start of therapy. End points were changes in HR variability (SD of normal-to-normal intervals, mean square of differences between consecutive R-R intervals), HR, deceleration capacity, and periodic repolarization dynamics as well as ventricular function and NT-proBNP (N-terminal pro-B-type natriuretic peptide). Of 63 patients with heart failure with reduced ejection fraction enrolled, 48 (76.2%) patients were still on ARNI at follow-up. SD of normal-to-normal intervals increased from 25 to 36 milliseconds ( P <0.001), mean square of differences between consecutive R-R intervals increased from 12 to 19 milliseconds ( P <0.001), HR decreased from 73±9 bpm to 67±4 bpm, ( P <0.001), and deceleration capacity increased from 2.1 to 4.4 milliseconds ( P <0.001). A trend for periodic repolarization dynamics reduction was observed (5.6 deg 2 versus 4.7 deg 2 , P =0.09). Autonomic changes were accompanied by increased left ventricular ejection fraction (29±6% versus 40±8%, P <0.001) and reduced NT-proBNP (3548 versus 685 ng/L, P <0.001). Correlation analysis showed a significant relationship between volume-unloading (as evidenced by NT-proBNP reduction) and autonomic improvement., Conclusions: Three months of ARNI therapy resulted in a significant increase in cardiac parasympathetic tone. The improvement in autonomic properties may be mediated by "volume unloading" and likely contributes to the beneficial effects of ARNI in heart failure with reduced ejection fraction., Registration: URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04587947.