title: Revealing the Concealed Nature of Long-QT Type 3 Syndrome.
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).
  
  
  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.
authors.affiliation: 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.).
authors.forename: Amara
authors.initials: A
authors.lastname: Greer-Short
authors.affiliation: 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.).
authors.forename: Sharon A
authors.initials: SA
authors.lastname: George
authors.affiliation: 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.
authors.forename: Steven
authors.initials: S
authors.lastname: Poelzing
authors.affiliation: 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.
authors.forename: Seth H
authors.initials: SH
authors.lastname: Weinberg
mesh_terms: D000200:Action Potentials; D000818:Animals; D000075224:Cardiac Conduction System Disease; D004195:Disease Models, Animal; D004487:Edema / Q000503:physiopathology; D006168:Guinea Pigs; D008133:Long QT Syndrome / Q000235:genetics / Q000503:physiopathology*; D008390:Markov Chains; D009154:Mutation; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics; D010641:Phenotype
chemical_list: D062554:NAV1.5 Voltage-Gated Sodium Channel
keywords: action potential; edema; long QT syndrome; mutation; sodium channels