Identifying an appropriate endpoint for cryoablation in children with atrioventricular nodal reentrant tachycardia: Is residual slow pathway conduction associated with recurrence?

BACKGROUND: Cryoablation is increasingly used to treat atrioventricular nodal reentrant tachycardia (AVNRT) due to its safety profile. However, cryoablation may have higher recurrence than radiofrequency ablation (RFA), and the optimal procedural endpoint remains undefined. OBJECTIVE: The purpose of this study was to identify the association of cryoablation procedural endpoints with postprocedural AVNRT recurrence. METHODS: We performed a single-center, retrospective analysis of pediatric patients following successful first-time cryoablation for AVNRT between January 1, 2011, and December 31, 2019. Preablation inducibility of AVNRT was recorded. Procedural endpoints, including slow pathway (SP) conduction (presence of jump or echo beats) with and without isoproterenol, were identified. Recurrence was established from clinical notes and/or direct patient contact. RESULTS: Of 256 patients, 147 (57%) were assessed on isoproterenol precryoablation, and 171 (47%) were assessed on isoproterenol postcryoablation. Mean cryolesion time was 2586 ± 1434 seconds. Following ablation, 104 (41%) had some evidence of residual SP conduction. With median follow-up time of 1.9 [0.7-3.7] years, recurrence occurred in 14 patients (5%). Complete elimination of SP conduction (with and without isoproterenol) had a hazard ratio for recurrence of 1.26 (95% confidence interval [CI] 0.42-3.8; P = .68) on univariate analysis and 1.39 (95% CI 0.36-5.4; P = .63) on multivariate analysis (including demographics, ablation time, 8-mm cryocatheter, and baseline inducibility). CONCLUSION: The observed AVNRT recurrence rate after cryoablation was comparable to that of RFA. The presence of residual SP conduction was not associated with recurrence. This suggests that jump or single echo beat may be an acceptable endpoint in AVNRT cryoablation.

An Adaptive Mutation in Enterococcus faecium LiaR Associated with Antimicrobial Peptide Resistance Mimics Phosphorylation and Stabilizes LiaR in an Activated State.

The cyclic antimicrobial lipopeptide daptomycin (DAP) triggers the LiaFSR membrane stress response pathway in enterococci and many other Gram-positive organisms. LiaR is the response regulator that, upon phosphorylation, binds in a sequence-specific manner to DNA to regulate transcription in response to membrane stress. In clinical settings, non-susceptibility to DAP by Enterococcus faecium is correlated frequently with a mutation in LiaR of Trp73 to Cys (LiaRW73C). We have determined the structure of the activated E. faecium LiaR protein at 3.2Å resolution and, in combination with solution studies, show that the activation of LiaR induces the formation of a LiaR dimer that increases LiaR affinity at least 40-fold for the extended regulatory regions upstream of the liaFSR and liaXYZ operons. In vitro, LiaRW73C induces phosphorylation-independent dimerization of LiaR and provides a biochemical basis for non-susceptibility to DAP by the upregulation of the LiaFSR regulon. A comparison of the E. faecalis LiaR, E. faecium LiaR, and the LiaR homolog from Staphylococcus aureus (VraR) and the mutations associated with DAP resistance suggests that physicochemical properties such as oligomerization state and DNA specificity, although tuned to the biology of each organism, share some features that could be targeted for new antimicrobials.