Angiotensin receptor-neprilysin inhibition and improved ventricular-arterial coupling in heart failure with reduced ejection fraction.

Abstract

Sacubitril/valsartan improves outcomes in chronic heart failure (HF) with reduced ejection fraction (EF). The underlying mechanisms on left ventricular (LV) myocardial function are incompletely understood. In this study, 117 patients with symptomatic HF and LVEF ≤ 40% were enrolled prospectively. Noninvasive pressure-volume analysis was calculated from transthoracic echocardiography with simultaneous arm-cuff blood pressure measurements. Primary outcome parameters were LV end-systolic elastance (E_es; a measure of LV contractility), effective arterial elastance (E_a; a measure of afterload), and the ventricular-arterial coupling ratio (E_a/E_es). The mean age was 65 ± 13 yr, 30% were female, and 54.7% had ischemic heart disease. During 6 mo of follow-up, eight patients died, three withdrew their consent, and four were lost to follow-up. About 102 patients were included in pressure-volume analyses. After 6 mo of sacubitril/valsartan treatment, E_es increased (0.66 mmHg/mL [IQR 0.45-0.94] vs. 0.78 mmHg/mL [IQR 0.57-1.10], P = 0.001), E_a decreased (1.76 mmHg/mL [IQR 1.48-2.13] vs. 1.62 mmHg/mL [IQR 1.36-1.96], P = 0.014), and the E_a/E_es ratio improved (2.52 [IQR 1.88-4.05] vs. 1.93 [IQR 1.50-2.63], P < 0.001). LV end-diastolic pressure and LV volumes were reduced, and LVEF increased from 33% to 43% (both P < 0.001). Clinical improvement occurred in NYHA functional class, NT-proBNP level, and 6-min walking distance. Change in LVEF correlated with change in E_es (r = 0.33, P = 0.0008), while change in NT-proBNP was associated with change in LV end-diastolic pressure (LVEDP) (r = 0.42, P < 0.0001). In conclusion, sacubitril/valsartan is associated with improved ventricular-arterial coupling by enhancing LV contractility and reducing afterload. Beyond LV reverse remodeling, optimized ventricular-arterial interaction may contribute to the favorable outcome of sacubitril/valsartan treatment in HF with reduced EF.NEW & NOTEWORTHY The study demonstrates that 6-mo treatment with sacubitril/valsartan in patients with heart failure with reduced ejection fraction is associated with increased left ventricular contractility, reduced afterload, and improved ventricular-arterial coupling. Together with reverse remodeling, these changes indicate a leftward shift of the operating left ventricular pressure-volume relationship. These data provide new insights into the understanding of pharmacological mechanisms in the failing heart and may facilitate tailored medical therapy.