title: Genetically engineered SCN5A mutant pig hearts exhibit conduction defects and arrhythmias.
abstract: SCN5A encodes the α subunit of the major cardiac sodium channel Na(V)1.5. Mutations in SCN5A are associated with conduction disease and ventricular fibrillation (VF); however, the mechanisms that link loss of sodium channel function to arrhythmic instability remain unresolved. Here, we generated a large-animal model of a human cardiac sodium channelopathy in pigs, which have cardiac structure and function similar to humans, to better define the arrhythmic substrate. We introduced a nonsense mutation originally identified in a child with Brugada syndrome into the orthologous position (E558X) in the pig SCN5A gene. SCN5A(E558X/+) pigs exhibited conduction abnormalities in the absence of cardiac structural defects. Sudden cardiac death was not observed in young pigs; however, Langendorff-perfused SCN5A(E558X/+) hearts had an increased propensity for pacing-induced or spontaneous VF initiated by short-coupled ventricular premature beats. Optical mapping during VF showed that activity often began as an organized focal source or broad wavefront on the right ventricular (RV) free wall. Together, the results from this study demonstrate that the SCN5A(E558X/+) pig model accurately phenocopies many aspects of human cardiac sodium channelopathy, including conduction slowing and increased susceptibility to ventricular arrhythmias.
authors.forename: David S
authors.initials: DS
authors.lastname: Park
authors.forename: Marina
authors.initials: M
authors.lastname: Cerrone
authors.forename: Gregory
authors.initials: G
authors.lastname: Morley
authors.forename: Carolina
authors.initials: C
authors.lastname: Vasquez
authors.forename: Steven
authors.initials: S
authors.lastname: Fowler
authors.forename: Nian
authors.initials: N
authors.lastname: Liu
authors.forename: Scott A
authors.initials: SA
authors.lastname: Bernstein
authors.forename: Fang-Yu
authors.initials: FY
authors.lastname: Liu
authors.forename: Jie
authors.initials: J
authors.lastname: Zhang
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Rogers
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
authors.forename: Larry A
authors.initials: LA
authors.lastname: Chinitz
authors.forename: Glenn I
authors.initials: GI
authors.lastname: Fishman
mesh_terms: D000818:Animals; D001145:Arrhythmias, Cardiac / Q000235:genetics* / Q000503:physiopathology; D001483:Base Sequence; D053840:Brugada Syndrome / Q000235:genetics* / Q000503:physiopathology; D000075224:Cardiac Conduction System Disease; D018389:Codon, Nonsense; D004195:Disease Models, Animal; D005818:Genetic Engineering; D006329:Heart Conduction System / Q000002:abnormalities* / Q000503:physiopathology; D006801:Humans; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D062554:NAV1.5 Voltage-Gated Sodium Channel / Q000235:genetics*; D034421:Sus scrofa
chemical_list: D018389:Codon, Nonsense; D062554:NAV1.5 Voltage-Gated Sodium Channel