Abstract (1) Aims Atrial fibrillation (AF) is the most common cardiac arrhythmia. 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 v 1.5, has been associated with increased atrial excitability and familial AF. (2) Methods We designed a new murine model carrying the Scn5a -M1875T mutation enabling us to study the effects of the Na v 1.5 mutation in detail in vivo and in vitro using patch clamp and microelectrode recording of atrial cardiomyocytes, optical mapping, ECG, echocardiography, gravimetry, histology and biochemistry. (3) Results Atrial cardiomyocytes from newly generated adult Scn5a -M1875T +/- mice showed a selective increase in the early (peak) cardiac sodium current, larger action potential amplitude and a faster peak upstroke velocity. Conduction slowing caused by the sodium channel blocker flecainide was less pronounced in Scn5a -M1875T +/- compared to wildtype atria. Overt hypertrophy or heart failure in Scn5a -M1875T +/- mice could be excluded. (4) Conclusion The Scn5a -M1875T point mutation causes gain-of-function of the cardiac sodium channel. Our results suggest increased atrial peak sodium current as a potential trigger for increased atrial excitability and thus AF. What’s new The point mutation M1875T in the C-terminal domain of the cardiac sodium channel Na v 1.5 causes an increase in early peak sodium current in left atria. The observed changes induced by this point mutation suggest an increase in peak sodium current as a cause of familial atrial fibrillation (AF). Our findings provide a possible explanation for the variable effectiveness of sodium channel blockers in patients with AF. Carriers of such sodium channel gain-of-function mutations may benefit more from tailored treatments. Graphical abstract

Increased early sodium current causes familial atrial fibrillation and dampens effect of flecainide