Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block

O'Reilly, M.; Sommerfeld, L. C.; O'Shea, C.; Broadway-Stringer, S.; Andaleeb, S.; Reyat, J. S.; Kabir, S. N.; Malinova, A.; Delbue, D.; Fortmueller, L.; Gehmlich, K.; Pavlovic, D.; Skryabin, B. V.; Holmes, A. P.; Kirchhof, P.; Fabritz, L.

doi:10.1101/2022.01.18.476646

bioRxiv · 10.1101/2022.01.18.476646

Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block

O'Reilly, M.·Sommerfeld, L. C.·O'Shea, C.·Broadway-Stringer, S.·Andaleeb, S.·Reyat, J. S.·Kabir, S. N.·Malinova, A.·Delbue, D.·Fortmueller, L.·Gehmlich, K.·Pavlovic, D.·Skryabin, B. V.·Holmes, A. P.·Kirchhof, P.·Fabritz, L.

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Abstract

(1) AimsAtrial 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 -subunit of the cardiac sodium channel Nav1.5, has been associated with increased atrial excitability and familial AF. (2) MethodsWe designed a new murine model carrying the Scn5a-M1875T mutation enabling us to study the effects of the Nav1.5 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) ResultsAtrial 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) ConclusionThe 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. Whats newO_LIThe point mutation M1875T in the C-terminal domain of the cardiac sodium channel Nav1.5 causes an increase in early peak sodium current in left atria. C_LIO_LIThe observed changes induced by this point mutation suggest an increase in peak sodium current as a cause of familial atrial fibrillation (AF). C_LIO_LIOur 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. C_LI Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

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O'Reilly, M., Sommerfeld, L. C., O'Shea, C., Broadway-Stringer, S., Andaleeb, S., Reyat, J. S., Kabir, S. N., Malinova, A., Delbue, D., Fortmueller, L., Gehmlich, K., Pavlovic, D., Skryabin, B. V., Holmes, A. P., Kirchhof, P., Fabritz, L.. 2022-01-20. Increased early sodium current provokes familial atrial fibrillation and reduces effectiveness of sodium channel block. https://doi.org/10.1101/2022.01.18.476646

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