Background

Atrial fibrillation (AF) is the most common cardiac arrhythmia. AF often develops due to concomitant cardiovascular conditions combined with a pre-existing atrial substrate. Familial, early onset forms of AF enable identification of this substrate. Pathogenic variants in genes encoding ion channels are associated with familial AF. The point mutation M1875T in the SCN5A gene, which encodes the α-subunit of the cardiac sodium channel Na_v1.5, has been associated with increased atrial excitability and familial AF. Designing a new murine model carrying the Scn5a -M1875T mutation enabled us to study this atrial substrate in detail.

Methods and Results

Left atrial cardiomyocytes from newly generated Scn5a-M1875T^+/- mice showed a selective increase in the early (peak) cardiac sodium current, measured by patch clamp (wildtype, WT: -22.7 ± 0.9 pA/pF, N=14 animals, n=115 cells; Scn5a-M1875T+/-: -28.3 ± 1.1 pA/pF, N=15, n=117). Microelectrode recordings of intact left atria revealed larger action potential amplitudes (WT: 86.4 ± 0.9 mV (N=8, n=24); Scn5a-M1875T+/-: 91.2 ± 0.7 mV, N=8, n=25) and a faster peak upstroke velocity (at 100 ms pacing cycle length, PCL: WT: 127.98 ± 3.28 mV/ms; Scn5a-M1875T+/-: 142.80 ± 3.98 mV/ms). Conduction was studied using optical mapping. When challenged with the sodium channel blocker flecainide, Scn5a-M1875T^+/- left atria showed less conduction slowing than matched wildtype atria (at 100 ms PCL: WT: -10.43 ± 1.26 cm/s, N=12; Scn5a-M1875T+/-: -6.10 ± 1.34 cm/s, N=12). In vivo analysis using electrocardiograms and echocardiography, as well as cardiac histology excluded overt hypertrophy or heart failure in young adults.

Conclusion

The Scn5a-M1875T point mutation causes a cardiac sodium channel gain-of-function and suggests increased atrial peak sodium current as a potential trigger for increased atrial excitability and atrial fibrillation.