Septal Substrate Ablation Guided by Delayed Transmural Conduction Times: A Novel Ablation Approach to Target Intramural Substrates.

BACKGROUND: Intraprocedural identification of intramural septal substrate for ventricular tachycardia (ISS-VT) in nonischemic cardiomyopathy (NICM) is challenging. Delayed (>40 ms) transmural conduction time (DCT) with right ventricular basal septal pacing has been previously shown to identify ISS-VT. OBJECTIVES: This study sought to determine whether substrate catheter ablation incorporating areas of DCT may improve acute and long-term outcomes. METHODS: We included patients with NICM and ISS-VT referred for catheter ablation between 2016 and 2020. ISS-VT was defined by the following: 1) confluent septal areas of low unipolar voltage (<8.3 mV) in the presence of normal or minimal bipolar abnormalities; and 2) presence of abnormal electrograms in the septum. Substrate ablation was guided by the following: 1) activation and/or entrainment mapping for tolerated VT and pace mapping with ablation of abnormal septal electrograms for unmappable VTs (n = 57, Group 1); and 2) empirically extended to target areas of DCT during right ventricular basal septal pacing regardless of their participation in inducible VT(s) but sparing the conduction system when possible (n = 24, Group 2). RESULTS: There were no significant baseline differences between Groups 1 and 2. Noninducibility of any VT programmed stimulation at the end of ablation was higher in Group 2 compared with Group 1 (80% vs 53%; P = 0.03). At 12-month follow-up, single-procedure VT-free survival was significantly higher (79% vs 46%; P = 0.006) and the time to VT recurrence was longer (mean 10 ± 3 months vs 7 ± 4 months; P = 0.02) in Group 2 compared with Group 1. CONCLUSIONS: In patients with NICM and ISS-VT, a substrate ablation strategy that incorporates areas of DCT appears to improve freedom from recurrent VT.

Transient Delivery of a KCNQ2/3-Specific Channel Activator 1 Week After Noise Trauma Mitigates Noise-Induced Tinnitus.

Exposure to loud noise can cause hearing loss and tinnitus in mice and humans. In mice, one major underlying mechanism of noise-induced tinnitus is hyperactivity of auditory brainstem neurons, due at least in part, to decreased Kv7.2/3 (KCNQ2/3) potassium channel activity. In our previous studies, we used a reflex-based mouse model of tinnitus and showed that administration of a non-specific KCNQ channel activator, immediately after noise trauma, prevented the development of noise-induced tinnitus, assessed 1 week after trauma. Subsequently, we developed RL-81, a very potent and highly specific activator of KCNQ2/3 channels. Here, to test the timing window within which RL-81 prevents tinnitus in mice, we modified and employed an operant animal model of tinnitus, where mice are trained to move in response to sound but not move in silence. Mice with behavioral evidence of tinnitus are expected to move in silence. We validated this mouse model by testing the effect of salicylate, which is known to induce tinnitus. We found that transient administration of RL-81 1 week after noise exposure did not affect hearing loss but reduced significantly the percentage of mice with behavioral evidence of tinnitus, assessed 2 weeks after noise exposure. Our results indicate that RL-81 is a promising drug candidate for further development for the treatment of noise-induced tinnitus.