Effects of BNP and Sacubitrilat/Valsartan on Atrial Functional Reserve and Arrhythmogenesis in Human Myocardium

Figures

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  Figure 1. Effect of BNP on atrial inotropy and lusitropy after adrenergic stimulation. Example traces of time-dependent analysis of BNP (n = 20 strips) are shown in (A), with the corresponding data on the effect of BNP treatment on atrial systolic force (B), and end-diastolic tension generation (C) after 70 min. The slope of end-diastolic tension over time is shown in (D). The effects of a frequency-variation protocol [example traces in (E), n = 40 strips] on systolic force at different stimulation frequencies are shown in (F,G). Correlation of patient plasma NTproBNP and relative force increase after ISO treatment (values from n = 19 patients with available NTproBNP) is shown in (H). Data are shown as mean ± SEM; each data point represents one muscle strip. In (H), each point represents the mean developed systolic force per patient. ISO, isoproterenol; BNP, brain natriuretic peptide.

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  Figure 2. Effect of Sac/Val on atrial inotropy and lusitropy after adrenergic stimulation. Example traces of a “frequency-variation protocol” in Sac-treated muscle strips (n = 15 strips) are shown in (A), with its effects on developed force during different frequencies shown in (B,C). Examples traces of a frequency-variation protocol in Sac/Val treated muscle strips (n = 24 strips) are shown in (D), with the corresponding effects on developed force in (E,F). The effects of Sac/Val on end-diastolic tension are shown as per stimulation frequency (G) and as the diastolic tension slope derived from linear regression (H). Data are shown as mean ± SEM; each data point represents one muscle strip. ISO, isoproterenol, Sac: Sacubitrilat; Val: valsartan; Veh: vehicle (DMSO).

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  Figure 3. Effect of BNP and Sac/Val on atrial arrhythmogenesis. (A) Representative traces of a protocol with constant stimulation at 1 Hz in strips treated with ISO ± BNP; the overall effect of BNP treatment on arrhythmogenesis in this protocol is shown in (B). For this analysis, three time intervals (25–30, 45–50, and 65–70 min) after ISO have been screened for arrhythmias. (C) Example traces for muscle strips treated with ISO ± BNP during the switch from 3 Hz to 0.5 Hz stimulation frequency in a “frequency-variation protocol” protocol. The effects of BNP on arrhythmogenesis at 0.5 Hz (D) and pooled over all time points (E) are shown. For this analysis, the arrhythmias at 1 Hz (10 min) and 2, 3, and 0.5 Hz (each 5 min) have been included Finally, example traces of muscle strips treated with a vehicle (DMSO) or Sac/Val at the transition between 1 and 2 Hz stimulation frequency are shown in (F), with the effects of Sac/Val treatment on arrhythmias at higher stimulation frequencies in (G) and the overall effect on arrhythmia in (H). For this analysis, the arrhythmias at 1 Hz (10 min) and 2, 3, and 0.5 Hz (each 5 min) have been included. ISO, isoproterenol; BNP, brain natriuretic peptide;…

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  Figure 4. NEP expression (in ng/mg of total protein) in human atrial and ventricular samples from patients with end-stage heart failure. NEP expression was analyzed in RA and LV biopsies from n = 10 patients with end-stage heart failure. NEP is equally expressed in the failing atrial and ventricular myocardium (A) and expression of atrial and ventricular NEP correlates in the patient cohort (B). LV NEP expression correlates inversely with LA volume (C) and RA NEP negatively correlates with patient NYHA (D). Each point represents data from one patient. NEP, Neprilysin; LV, left ventricle; LA, left atrium; RA, right atrium.