Sacubitril/Valsartan Improves Autonomic Function and Cardiopulmonary Parameters in Patients with Heart Failure with Reduced Ejection Fraction.

Background: Heart rate recovery (HRR) is a marker of vagal tone, which is a powerful predictor of mortality in patients with cardiovascular disease. Sacubitril/valsartan (S/V) is a treatment for heart failure with reduced ejection fraction (HFrEF), which impressively impacts cardiovascular outcome. This study aims at evaluating the effects of S/V on HRR and its correlation with cardiopulmonary indexes in HFrEF patients. Methods: Patients with HFrEF admitted to outpatients' services were screened out for study inclusion. S/V was administered according to guidelines. Up-titration was performed every 4 weeks when tolerated. All patients underwent laboratory measurements, Doppler-echocardiography, and cardiopulmonary exercise stress testing (CPET) at baseline and at 12-month follow-up. Results: Study population consisted of 134 HFrEF patients (87% male, mean age 57.9 +/- 9.6 years). At 12-month follow-up, significant improvement in left ventricular ejection fraction (from 28% +/- 5.8% to 31.8% +/- 7.3%,p< 0.0001), peak exercise oxygen consumption (VO2peak) (from 15.3 +/- 3.7 to 17.8 +/- 4.2 mL/kg/min,p< 0.0001), the slope of increase in ventilation over carbon dioxide output (VE/VCO2 slope)(from 33.4 +/- 6.2 to 30.3 +/- 6.5,p< 0.0001), and HRR (from 11.4 +/- 9.5 to 17.4 +/- 15.1 bpm,p= 0.004) was observed. Changes in HRR were significantly correlated to changes in VE/VCO2slope(r= -0.330;p= 0.003). After adjusting for potential confounding factors, multivariate analysis showed that changes in HRR were significantly associated to changes in VE/VCO2slope(Beta (B) = -0.975, standard error (SE) = 0.364, standardized Beta coefficient (Bstd) = -0.304,p= 0.009). S/V showed significant reduction in exercise oscillatory ventilation (EOV) detection at CPET (28 EOV detected at baseline CPET vs. 9 EOV detected at 12-month follow-up,p< 0.001). HRR at baseline CPET was a significant predictor of EOV at 12-month follow-up (B = -2.065, SE = 0.354,p< 0.001). Conclusions: In HFrEF patients, S/V therapy improves autonomic function, functional capacity, and ventilation. Whether these findings might translate into beneficial effects on prognosis and outcome remains to be elucidated.