Meta-Analysis of Effects of Digoxin on Survival in Patients with Atrial Fibrillation or Heart Failure: An Update.

In 2015, 3 independent meta-analyses raised concerns about digoxin therapy being associated with an increased mortality risk in patients with atrial fibrillation (AF) and with heart failure (HF). Although several other studies have been published since then fostering these safety issues, the most recent 2016 European guidelines for AF still recommend this therapy as a class I indication. We performed an updated systematic review and random-effect meta-analysis on publications up to March 2018 reporting data on digoxin associated mortality in subjects with AF or HF. Based on the adjusted survival data of all identified 37 trials comprising a total of 825,061 patients, digoxin use was associated with an increased relative risk of all-cause mortality (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.05 to 1.29, p <0.01). Treatment with digoxin was associated with an increased mortality risk in the subgroup of patients with AF (n = 627,620, HR 1.23, 95% CI, 1.17 to 1.30, p <0.01), and in the subgroup of patients with HF (n = 197,441, HR 1.11, 95% CI, 1.06 to 1.16, p<0.01). A sensitivity analysis of studies reporting data on new digoxin users (n = 41,687) demonstrated an even higher risk for all-cause mortality compared with patients not receiving cardiac glycosides (HR 1.47, 95% CI, 1.15 to 1.88, p <0.01). In conclusion, this updated meta-analysis confirms that digoxin use is associated with increased mortality in patients with AF or HF.

Status epilepticus in the immature rodent brain alters the dynamics of autophagy.

There is considerable interest in defining the molecular pathways involved in seizure-induced neuronal death. Necrotic, apoptotic and anti-apoptotic signalling pathways are activated after status epilepticus (SE). Analyses of apoptosis and necrosis have been merely reported, however conditions of autophagic cell death with hallmarks of type 2 programmed cell death-morphology are relatively few. Autophagy is a highly regulated cellular mechanism for the bulk degradation of cytoplasmic contents which is involved in a variety of physiological and pathological conditions associated with neurological diseases. Our goal was to examine whether autophagy is implicated in the cell death machinery after SE. For this purpose, we used lithium-pilocarpine model of SE in 14-day-old rats and examined the dynamics in the expression of autophagic markers in the hippocampus in controls and in animals subjected to SE at 6, 24, and 48h after the insult. Protein levels of central components of the autophagic machinery were dramatically affected by SE with, however, altered dynamics, compared to controls. Levels of LC3, phospho-mTOR/mTOR, BAG3 and Hsp70 were significantly increased, whereas Beclin 1 levels remained unchanged after SE. The dynamics in the expression of Atg3, Atg5, Atg7, Atg14 and LAMP1 were slightly altered. The amount of SQSTM1/p62 underwent a dramatic and highly significant breakdown 48 h after the induction of SE. These results demonstrate for the first time that SE in the immature brain results in significant alterations of autophagy dynamics. There is a growing interest in the role of autophagy in neurodegeneration, and an emerging consensus that autophagy represents a double-edged sword, acting either as a prosurvival mechanism, or as part of a cell death pathway.