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Circ Arrhythm Electrophysiol. 2017 Feb;10(2):e004400. doi: 10.1161/CIRCEP.116.004400.

Revealing the Concealed Nature of Long-QT Type 3 Syndrome.

Author information

1
From the Virginia Tech Carilion Research Institute, Virginia Polytechnic Institute and State University, Roanoke (A.G.-S., S.A.G., S.P.); and Department of Biomedical Engineering, Virginia Commonwealth University, Richmond (S.H.W.).
2
From the Virginia Tech Carilion Research Institute, Virginia Polytechnic Institute and State University, Roanoke (A.G.-S., S.A.G., S.P.); and Department of Biomedical Engineering, Virginia Commonwealth University, Richmond (S.H.W.). shweinberg@vcu.edu poelzing@vtc.vt.edu.

Abstract

BACKGROUND:

Gain-of-function mutations in the voltage-gated sodium channel (Nav1.5) are associated with the long-QT-3 (LQT3) syndrome. Nav1.5 is densely expressed at the intercalated disk, and narrow intercellular separation can modulate cell-to-cell coupling via extracellular electric fields and depletion of local sodium ion nanodomains. Models predict that significantly decreasing intercellular cleft widths slows conduction because of reduced sodium current driving force, termed "self-attenuation." We tested the novel hypothesis that self-attenuation can "mask" the LQT3 phenotype by reducing the driving force and late sodium current that produces early afterdepolarizations (EADs).

METHODS AND RESULTS:

Acute interstitial edema was used to increase intercellular cleft width in isolated guinea pig heart experiments. In a drug-induced LQT3 model, acute interstitial edema exacerbated action potential duration prolongation and produced EADs, in particular, at slow pacing rates. In a computational cardiac tissue model incorporating extracellular electric field coupling, intercellular cleft sodium nanodomains, and LQT3-associated mutant channels, myocytes produced EADs for wide intercellular clefts, whereas for narrow clefts, EADs were suppressed. For both wide and narrow clefts, mutant channels were incompletely inactivated. However, for narrow clefts, late sodium current was reduced via self-attenuation, a protective negative feedback mechanism, masking EADs.

CONCLUSIONS:

We demonstrated a novel mechanism leading to the concealing and revealing of EADs in LQT3 models. Simulations predict that this mechanism may operate independent of the specific mutation, suggesting that future therapies could target intercellular cleft separation as a compliment or alternative to sodium channels.

KEYWORDS:

action potential; edema; long QT syndrome; mutation; sodium channels

PMID:
28213505
PMCID:
PMC5319726
DOI:
10.1161/CIRCEP.116.004400
[Indexed for MEDLINE]
Free PMC Article

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