Triggered activity in atrial myocytes is influenced by Na⁺/Ca²⁺ exchanger activity in genetically altered mice

In atrial fibrillation, increased function of the Na⁺/Ca²⁺-exchanger (NCX) is one among several electrical remodeling mechanisms.

Using the patch-clamp- and Ca²⁺ imaging-methods, we investigated atrial myocytes from NCX-homozygous-overexpressor (OE)- and heterozygous-knockout (KO)-mice and their corresponding wildtypes (WT_OE; WT_KO). NCX mediated Ca²⁺ extrusion capacity was reduced in KO and increased in OE. There was no evidence for structural or molecular remodeling. During a proarrhythmic pacing-protocol, the number of low amplitude delayed afterdepolarizations (DADs) was unaltered in OE vs. WT_OE and KO vs. WT_KO. However, DADs triggered full spontaneous action potentials (sAP) significantly more often in OE vs. WT_OE (ratio sAP/DAD: OE:0.18±0.05; WT_OE:0.02±0.02; p<0.001). Using the same protocol, a DAD triggered an sAP by tendency less often in KO vs. WT_KO (p=0.06) and significantly less often under a more aggressive proarrhythmic protocol (ratio sAP/DAD: KO:0.01±0.003; WT KO: 0.12±0.05; p=0.007). The DAD amplitude was increased in OE vs. WT_OE and decreased in KO vs. WT_KO. There were no differences in SR-Ca²⁺-load, the number of spontaneous Ca²⁺-release-events or IKACh/IK1.

Atrial myocytes with increased NCX expression exhibited increased vulnerability towards sAPs while atriomyocytes with reduced NCX expression were protected. The underlying mechanism consists of a modification of the DAD-amplitude by the level of NCX-activity. Thus, although the number of spontaneous Ca²⁺-releases and therefore DADs is unaltered, the higher DAD-amplitude in OE made a transgression of the voltage-threshold of an sAP more likely. These findings indicate that the level of NCX activity could influence triggered activity in atrial myocytes independent of possible remodeling processes.