Cardiac sodium channels are responsible for conduction in the normal and diseased heart. We aimed to investigate regional and transmural distribution of sodium channel expression and function in the myocardium. Sodium channel Scn5a mRNA and Na v 1.5 protein distribution was investigated in adult and embryonic mouse heart through immunohistochemistry and in situ hybridization. Functional sodium channel availability in subepicardial and subendocardial myocytes was assessed using patch-clamp technique. Adult and embryonic (ED14.5) mouse heart sections showed low expression of Na v 1.5 in the HCN4-positive sinoatrial and atrioventricular nodes. In contrast, high expression levels of Na v 1.5 were observed in the HCN4-positive and Cx43-negative AV or His bundle, bundle branches and Purkinje fibers. In both ventricles, a transmural gradient was observed, with a low Na v 1.5 labeling intensity in the subepicardium as compared to the subendocardium. Similar Scn5a mRNA expression patterns were observed on in situ hybridization of embryonic and adult tissue. Maximal action potential upstroke velocity was significantly lower in subepicardial myocytes (mean ± SEM 309 ± 32 V/s; n = 14) compared to subendocardial myocytes (394 ± 32 V/s; n = 11; P \ 0.05), indicating decreased sodium channel availability in subepicardium compared to subendocardium. Scn5a and Na v 1.5 show heterogeneous distribution patterns within the cardiac conduction system and across the ventricular wall. This differential distribution of the cardiac sodium channel may have profound consequences for conduction disease phenotypes and arrhythmogenesis in the setting of sodium channel disease.

In the mouse, ventricular myocardium activation and early repolarization waves are simultaneously present. This hampers unequivocal interpretation of the duration of the QRS complex as a measure of ventricular activation duration, especially when conduction is slowed. Under these conditions mapping of local activation and repolarization patterns is required for correct interpretation of the ECG.

Depending on the diagnostic criteria used, the Brugada syndrome was observed in 3% to 24% of patients with idiopathic ventricular fibrillation, underlining the importance of defining the precise diagnostic criteria in these patients. For all idiopathic ventricular fibrillation patients, the ventricular tachyarrhythmia recurrence rate was substantial during an average follow-up of more than 6 years.

Funding Acknowledgements Type of funding sources: None. Background Atrial fibrillation (AF) is characterized by complex electrical, structural and metabolic remodelling. The mechanisms underlying AF progression from paroxysmal to persistent AF are not fully understood, and studies in cardiomyocytes (CMs) at the paroxysmal stage of AF are lacking. Moreover, most studies have so far investigated right atrial appendage CMs, while left atrial appendage (LAA) CMs may be more informative, as AF is predominantly a left atrial disease. Whether and to what extent electrical remodelling during various AF stages also includes alterations of the (late) sodium current (INa), remains unclear. Moreover, the functional relevance of sodium channel isoforms other than the cardiac Nav1.5, such as the "neuronal" isoform SCN10A/NaV1.8, during the various stages of AF is as yet not fully elucidated. Purpose To investigate peak and late INa remodelling in LAA CMs from patients with paroxysmal and persistent AF and patients in sinus rhythm (SR), as well as the potential contribution of NaV1.8-based current. Methods LAA were obtained from patients in SR (N=18) without a history of AF undergoing cardiac surgery, as well as from patients with paroxysmal (N=12) and persistent AF (N=30). Paroxysmal AF was defined as AF episodes terminating spontaneously within seven days and persistent as AF continuing for more than 7 days but less than 1 year. Peak INa, late INa and action potential (AP) properties were investigated through patch-clamp analysis on single LAA CMs, while qPCR was used to assess SCN5A and SCN10A expression levels in LAA tissue. Results In paroxysmal and persistent AF CMs, AP duration was shorter than in SR CMs. Compared to SR, peak INa (Figure 1A) and SCN5A expression (Figure 1B) were significantly decreased in paroxysmal AF, while they were restored to SR levels in persistent AF. Conversely, while late INa was undetectable in SR and paroxysmal AF, it was significantly increased in persistent AF (Figure 2). Peak and late INa Nav1.8-based current was not detected in persistent AF CMs. Similarly, expression of SCN10A was not observed in LAAs at any stage. Conclusions Our study is the first to show that AP shortening already occurs in LAA CMs from paroxysmal AF, potentially contributing to pro-arrhythmia in this early stage of the disease. Moreover, our findings demonstrate that INa is differentially remodelled during various stages of AF, with peak INa reduction occurring during paroxysmal AF, while late INa is increased in persistent AF only. Finally, we have shown that Nav1.8 current does not contribute to the AF-related alterations in INa. These observations are of particular relevance when considering potential pharmacological approaches targeting (late) INa in patients with distinct forms of AF.