Influence of flecainide on atrial electrophysiology in rabbits maintained on normal versus high-cholesterol
M Klis, I Kotadia, N Bodagh, V Vigneswaran, K Maciunas, A Von Kietzell, A Gharaviri, A Barr, E Boland, I Sim, J Whitaker, M Shattock, J Keen, M O'neill, S E WilliamsAbstract
Background
Flecainide is a class Ic antiarrhythmic drug commonly used in management of supraventricular tachycardias, yet its effects on atrial electrophysiology remain incompletely understood. Elevated cholesterol levels can alter cardiac electrophysiological properties but their influence on the atrial response to flecainide is unclear. This study examined conduction velocity (CV), action potential duration (APD), and anisotropy in rabbits maintained on normal versus high-cholesterol diets before and after flecainide exposure.
Methods
Nine adult male New Zealand White rabbits were randomised to - four fed a 0.75% cholesterol diet for six weeks and five controls on standard chow. After six weeks, left atrial tissue was isolated, perfused, and optically mapped during pacing at 100 and 150 bpm. Following baseline recordings, preparations were superfused with 1 µM flecainide for ten minutes and remapped using the same pacing protocol. Optical data was analysed in ElectroMap to derive CV and APD at 50% repolarisation. Conduction anisotropy was assessed in MATLAB by fitting a plane to local activation times within 5×5-pixel patches, deriving conduction velocities along x- and y-axes. As true fiber orientation was unknown, the absolute deviation of each pixel’s anisotropy ratio from 1 (i.e., |AR–1|) was calculated to quantify deviation from isotropy. Linear mixed models with Type III ANOVA assessed effects of diet, flecainide, and their interaction. Results were calculated per observation and are presented as mean ± standard deviation.
Results
Baseline CV was similar between groups (44.1±1.9 ms in cholesterol vs 43.6±1.7 ms in controls, p = 0.99) and showed a mild, non-significant reduction after flecainide in both groups (42.1 and 42.5 ms, p = 0.10). Cholesterol-fed rabbits had longer APD than controls at baseline (33.3±3.41 vs 29.8±2.63 ms, p = 0.01). APD shortening after flecainide was seen only in the control group but not in cholesterol group (group × drug interaction, p = 0.01). Baseline anisotropy ratios were comparable between groups (0.76 vs 0.71, p = 0.32), but after flecainide, cholesterol-fed rabbits showed a significant reduction in anisotropy evidenced by increased median deviation from isotropy (−0.027 ± 0.023, p = 0.03), whereas controls were largely unchanged. These findings indicate that flecainide affects atrial anisotropy selectively in a hypercholesterolemic context.
Conclusions
High cholesterol diet prolongs atrial repolarisation and modifies the anisotropic response to flecainide without affecting conduction velocity. The increased deviation from isotropy in cholesterol-fed rabbits suggests that structural or functional remodelling as a sequela of a diet high in cholesterol may interact with drug effects, potentially contributing to arrhythmogenic vulnerability.