I(f) blocking potency of ivabradine is preserved under elevated endotoxin levels in human atrial myocytes

Lower heart rate is associated with better survival in patients with multiple organ dysfunction syndrome (MODS), a disease mostly caused by sepsis. The benefits of heart rate reduction by ivabradine during MODS are currently being investigated in the MODI(f)Y clinical trial. Ivabradine is a selective inhibitor of the pacemaker current I(f) and since I(f) is impaired by lipopolysaccharide (LPS, endotoxin), a trigger of sepsis, we aimed to explore I(f) blocking potency of ivabradine under elevated endotoxin levels in human atrial cardiomyocytes. Treatment of myocytes with S-LPS (containing the lipid A moiety, a core oligosaccharide and an O-polysaccharide chain) but not R595 (an O-chain lacking LPS-form) caused I(f) inhibition under acute and chronic septic conditions. The specific interaction of S-LPS but not R595 to pacemaker channels HCN2 and HCN4 proves the necessity of O-chain for S-LPS–HCN interaction. The efficacy of ivabradine to block I(f) was reduced under septic conditions, an observation that correlated with lower intracellular ivabradine concentrations in S-LPS- but not R595-treated cardiomyocytes. Computational analysis using a sinoatrial pacemaker cell model revealed that despite a reduction of I(f) under septic conditions, ivabradine further decelerated pacemaking activity. This novel finding, i.e. I(f) inhibition by ivabradine under elevated endotoxin levels in vitro, may provide a molecular understanding for the efficacy of this drug on heart rate reduction under septic conditions in vivo, e.g. the MODI(f)Y clinical trial.