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.

View original source ↗Export metadata ↓

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

Source connections

Published article ↗

Explore related subjects

molecular biology Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

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

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Trans-branching of polyubiquitin chains orchestrates the DNA replication stress response

Polyubiquitin chain geometry dictates functional consequences of ubiquitylation. Although branched polyubiquitin chains are abundant in cells, little is known about their functions. Here we show that branching on the DNA replication factor PCNA, mediated by the ubiquitin-conjugating enzyme UBE2K and involving lysines 63 and 48 of ubiquitin, orchestrates the sequence of events in response to replication stress. By inducing VCP-dependent extraction of PCNA from chromatin, branching promotes re-priming of stalled forks and necessitates a BRCA1-dependent pathway of daughter-strand gap repair. Our study identifies hyper-accumulation of daughter-strand gaps as the mechanistic basis underlying the toxicity of inhibitors of the PCNA-specific isopeptidase, USP1, in BRCA1-deficient cells. Moreover, an unexpected preference of UBE2K to operate in trans suggests a general timing mechanism to organize hierarchies amongst ubiquitin signals.

molecular biology↗

bioRxiv2026

Impaired proteostasis is an early feature of the diabetic heart in humans and mice

Diabetes and obesity increase cardiac lipid levels leading to cardiomyopathy and heart failure. We hypothesized that intermittent fasting would reduce cardiac lipid levels. Surprisingly, intermittent fasting increased myocardial triglyceride content, but rescued mortality and attenuated cardiomyopathy in mice overexpressing cardiomyocyte acyl-CoA synthetase 1 (MHC-ACSL1). Lipid overload caused cardiomyocyte accumulation of polyubiquitinated protein aggregates containing desmin, a scaffolding intermediate filament protein, which intermittent fasting prevented. Furthermore, intermittent fasting reversed elevated myocardial C16:0 ceramide content, and knockdown of ceramide synthase CerS5 and CerS6 reduced palmitate-induced protein aggregation, highlighting a role for C16:0 ceramides in this pathology. Conversely, impairing aggrephagy with cardiomyocyte-specific p62 ablation induced heart failure in mice fed a high-fat diet, with paradoxically reduced cardiac lipid content. Crucially, non-failing diabetic human hearts also exhibited protein aggregate pathology. Taken together, these results demonstrate that impaired proteostasis characterizes cardiomyopathy from cardiac lipid overload and identify a promising new therapeutic target for this condition.

molecular biology↗

bioRxiv2026

Spatial profiling and neurovascular communication in the developing and adolescent cortex following prenatal alcohol exposure

Fetal alcohol spectrum disorders (FASD) constitute a wide range of developmental, cognitive, and behavioral impairments caused by prenatal alcohol exposure (PAE). Although neuronal and vascular consequences of PAE have been studied, how alcohol affects the cerebrovasculature within the framework of the neurovascular unit (NVU) across development remains poorly understood. At minimum, the NVU comprises neurons, astrocyte endfeet, and endothelial cells (ECs), which coordinate to maintain brain homeostasis. Here, we used the NanoString Digital Spatial Profiling platform to characterize spatial transcriptomic data from neurons, astrocytes, and ECs from PAE and saccharin (SAC) control cortices at embryonic day 18 (E18) and postnatal day 28 (P28). Differentially expressed genes were then used for Ingenuity Pathway Analysis (IPA) to identify altered biological pathways and perform comparison analyses across developmental time points, while CellChat was used to infer cell cell communication networks. We uncovered thousands of differentially expressed genes and numerous altered pathways and biological processes in PAE cortices across development. Both IPA and CellChat analyses implicated dysregulation of vascular and extracellular matrix (ECM) remodeling, cell adhesion, and neuroinflammatory signaling. CellChat further predicted the loss of several key bidirectional relationships and altered ligand-receptor interactions among neurovascular cell types at E18 and P28. Overall, these findings identify PAE associated alterations in neurovascular gene expression and intercellular signaling across development, providing potential mechanisms by which PAE may disrupt neurodevelopment.

molecular biology↗