Targeted ablation therapy for treatment of gastrointestinal dysrhythmias

Abstract

Bioelectrical slow waves are one of the main coordination mechanisms of gastric motility. Slow wave dysrhythmias occur in gastric motility disorders, offering a potential therapeutic target. This thesis aimed to investigate the feasibility and safety of using radio-frequency (RF) ablation to modulate slow wave activity, as a potential future therapeutic option. In-vivo experiments were designed and performed in weaner pigs. RF-ablation was performed on the gastric serosa in temperature-control mode, with a non-irrigated catheter. Baseline and post-ablation slow wave propagation was recorded with high-resolution electrical mapping (256 electrodes; 4 mm spacing). Histological and gross image analysis was performed on ablated tissue, and immunohistochemistry was employed to study the effect of ablation on interstitial cells of Cajal (ICC). First, the feasibility of modulating gastric slow wave propagation using ablation was investigated (n=15 pigs, 29 experiments). Ablations were performed as adjacent points forming a line, encompassing a range of parameters (55-85 ◦C, 5-10 s/point). The effective temperature range of RF-ablation was defined as 65-75 ◦C for 5-10 s/point, capable of inducing complete conduction blocks defined by high-resolution mapping, while maintaining the tissue integrity confirmed by histological analysis. Second, ablation was employed to eliminate normal and ectopic gastric pacemakers (n=13, 70 ◦C, 5 s/point, in the shape of a box around the pacemaker). Normal gastric pacemakers (n=6), were eliminated by ablation and resulted in the emergence of a new pacemaker site immediately distal to the original site. Similarly, ectopic pacemakers were eliminated in all cases (n=7), with the surrounding mapped area entrained by normal antegrade activity in 5 of those cases. Ablation lesions were localised to the site of the ablation, with localised disruption of the ICC network through the lesions. Finally, the safety and feasibility of gastric ablation in modulating slow wave conduction after two-weeks of healing was investigated using two groups: sham-ablation (n=3, roomtemperature, 5 s/point) and RF-ablation (n=3; 65 ◦C, 5 s/point). After initial surgery and ablation, the animals were recovered for two-weeks. In the final surgery, high-resolution mapping was repeated showing that the conduction block was sustained after two-weeks in all cases of the RF-ablation, whereas all cases of the sham-ablation had no conduction block. After two-weeks, the lesions were in the inflammation and proliferation phase, and ICC remained depleted and/or deformed within the ablation lesions. This thesis presents the feasibility of using RF ablation to modulate gastric slow wave activity and to eliminate ectopic and normal pacemakers, with safety and efficacy extending through the two-week post-surgical period.