Pro-arrhythmic Effect of Blocking the Small Conductance Calcium Activated Potassium Channel in Isolated Canine Left Atrium

Abstract

Background: Small conductance calcium activated potassium (SKCa) channels are voltage insensitive and are activated by intracellular calcium. Genome-wide association studies revealed that a variant of SKCa is associated with lone atrial fibrillation in humans. Roles of SKCa in atrial arrhythmias remain unclear. Objective: To determine roles of SKCa in atrial arrhythmias. Methods: Optical mapping using the isolated canine left atrium was performed. The optical action potential duration (APD) and induction of arrhythmia were evaluated before and after the addition of specific SKCa blockers-apamin or UCL-1684. Results: SKCa blockade significantly increased APD₈₀ (188 ± 19 ms vs 147 ± 11 ms; P<.001). The pacing cycle length thresholds to induce 2:2 alternans, and wave breaks were prolonged by SKCa blockade. Increased APD heterogeneity was observed after the SKCa blockade, as measured by the difference between the maximum and the minimum APD (39 ± 4 ms vs 26 ± 5 ms; P<.05), by standard deviation (12.43 ± 2.36 ms vs 7.49 ± 1.47 ms; P<.001), or by coefficient of variation (6.68% ± 0.97% vs 4.90% ± 0.84%; P<.05). No arrhythmia was induced at baseline by an S1-S2 protocol. After SKCa blockade, 4 of 6 atria developed arrhythmia. Conclusions: SKCa blockade promotes arrhythmia and prolongs the pacing cycle length threshold of 2:2 alternans and wave breaks in the canine left atrium. The proarrhythmic effect could be attributed to increased APD heterogeneity in the canine left atrium. This study provides supportive evidence of genome-wide association studies showing association of KCNN3 and lone atrial fibrillation.