Atrial dysfunction and remodeling are closely associated with new onset heart failure (HF), atrial fibrillation (AF) and an overall increased mortality. In clinical studies, LCZ696 (Sacubitril/Valsartan) has positive effects on cardiac remodeling and contractile function in ventricular myocardium as well as on left atrial (LA) remodeling. The active metabolite of sacubitril, LBQ657 (sacubitrilat), contributes to this effect by inhibiting neprilysin (NEP), which increases natriuretic peptide (NP) bioavailability. In the present study we investigate firstly the effect of BNP and secondly the effect of Sacubitrilat (LBQ657)/Valsartan on atrial function and arrhythmias in response to isoproterenol (Iso) and increased stimulation frequency in human myocardium.

Human myocardium treated with BNP did not alter developed force or twitch contraction/relaxation kinetics at 1 Hz vs. Iso alone (Patients=16; n=42 muscle strips). In muscles treated with Iso+BNP vs. Iso over 70 minutes at 1 Hz, diastolic tension (dT) increased over time in the Iso group (Patients=7; n=11 strips). However, dT dropped in the Iso+BNP group (Patients=5; n=8 strips), with significant differences from 20 min after BNP wash-in until the end of the protocol. In a protocol of increasing stimulation frequency and recovery (2 and 3 Hz, followed by 0.5 Hz), muscles treated with Iso+BNP (n=22) did not show significant differences in developed systolic force when compared to strips only treated with Iso (n=20 strips). However, muscle strips treated with Iso+BNP showed a significant reduction of diastolic tension at higher stimulation frequencies and recovery. In addition, the prevalence for arrhythmias (aftercontractions/minute) was lower in the Iso+BNP group in comparison to the Iso group. Sacubitrilat (LBQ657)/Valsartan did not affect developed systolic force in a protocol of increased stimulation frequency and recovery. Furthermore, diastolic tension was unchanged at higher stimulation frequencies while in the recovery phase it tented to be improved compared to control group. Detected arrhythmias were lower in the Sacubitrilat (LBQ657)/Valsartan group at higher stimulation frequencies.

Our results suggest an improved recovery of diastolic tension in the presence of BNP after adrenergic stimulation and therefore a cardioprotective short-term effect of BNP. The lower probability of arrhythmias after cardiac stress aligns with this hypothesis, but it could also indicate a direct antiarrhythmic effect of BNP. Furthermore, we demonstrated that Sacubitrilat (LBQ657)/Valsartan reduced arrhythmias at higher stimulation frequencies in human myocardium.