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- W2479953071 abstract "Gain-of-function mutations in the cardiac voltage-gated sodium channel (Nav1.5) are associated with the long QT-3 (LQT3) syndrome. Early afterdepolarizations (EADs) are common in isolated myocyte models of LQT3, but rare in tissue and patients with LQT3 mutations. We have shown that Nav1.5 is densely expressed at the intercalated disk and narrowing intercellular separation can support an alternative form of cell-to-cell coupling known as ephaptic coupling (EpC). EpC occurs when sodium channels in the depolarizing cell decrease the intercellular cleft potential, depolarizing the apposing membrane from the extracellular rather than the intracellular domain. Critically, EpC models predict that decreasing intercellular separation slows conduction due to reduced sodium current driving force. Here, we test the novel hypothesis that ephaptic self-attenuation can “mask” the LQT3 phenotype by reducing the driving force and late sodium current that produces EADs.We tested our hypothesis both in a pharmacological LQT3 model in isolated guinea pig hearts experiments (n=3), paced at 500 ms basic cycle length using late sodium current agonist ATXII (7nM), and a computational model. Acute interstitial edema, induced by 20 g/l mannitol, increased intercellular cleft width but did not alter action potential duration (APD). ATXII prolonged APD by 80±11 ms, and ATXII plus mannitol prolonged APD by 165±7 ms and produced EADs. In a computational model incorporating EpC, a recent LRd formulation, and a sodium channel LQT3-associated mutant model, we show that for wide clefts, mutant myocytes consistently produce EADs, while for small clefts and wild-type myocytes, EADs are suppressed. For both large and small widths, the mutant sodium channel incompletely inactivates, but only for small cleft widths is late sodium current sufficiently reduced, suppressing EADs. These data demonstrate that intercellular edema in LQT3 underlies the formation of EADs presumably by an ephaptically-mediated mechanism." @default.
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- W2479953071 date "2016-02-01" @default.
- W2479953071 modified "2023-09-27" @default.
- W2479953071 title "Ephaptic Self-Attenuation Conceals Early Afterdepolarizations Associated with Long QT-3 Syndrome" @default.
- W2479953071 doi "https://doi.org/10.1016/j.bpj.2015.11.1492" @default.
- W2479953071 hasPublicationYear "2016" @default.
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