title: Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1.
abstract: The long QT syndrome (LQTS) is a heritable disorder that predisposes to sudden cardiac death. LQTS is caused by mutations in ion channel genes including HERG and KCNE1, but the precise mechanisms remain unclear. To clarify this situation we injected adenoviral vectors expressing wild-type or LQT mutants of HERG and KCNE1 into guinea pig myocardium. End points at 48-72 h included electrophysiology in isolated myocytes and electrocardiography in vivo. HERG increased the rapid component, I(Kr), of the delayed rectifier current, thereby accelerating repolarization, increasing refractoriness, and diminishing beat-to-beat action potential variability. Conversely, HERG-G628S suppressed I(Kr) without significantly delaying repolarization. Nevertheless, HERG-G628S abbreviated refractoriness and increased beat-to-beat variability, leading to early afterdepolarizations (EADs). KCNE1 increased the slow component of the delayed rectifier, I(Ks), without clear phenotypic sequelae. In contrast, KCNE1-D76N suppressed I(Ks) and markedly slowed repolarization, leading to frequent EADs and electrocardiographic QT prolongation. Thus, the two genes predispose to sudden death by distinct mechanisms: the KCNE1 mutant flagrantly undermines cardiac repolarization, and HERG-G628S subtly facilitates the genesis and propagation of premature beats. Our ability to produce electrocardiographic long QT in vivo with a clinical KCNE1 mutation demonstrates the utility of somatic gene transfer in creating genotype-specific disease models.
authors.affiliation: Institute for Molecular Cardiobiology, The Johns Hopkins University, 720 Rutland Avenue, Baltimore, MD 21205, USA.
authors.forename: U C
authors.initials: UC
authors.lastname: Hoppe
authors.forename: E
authors.initials: E
authors.lastname: Marbán
authors.forename: D C
authors.initials: DC
authors.lastname: Johns
mesh_terms: D000200:Action Potentials; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D027682:Cation Transport Proteins; D016757:Death, Sudden, Cardiac; D004195:Disease Models, Animal; D004553:Electric Conductivity; D004562:Electrocardiography; D051638:Ether-A-Go-Go Potassium Channels; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000235:genetics; D006168:Guinea Pigs; D006339:Heart Rate; D008133:Long QT Syndrome / Q000150:complications / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology*; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism; D015221:Potassium Channels / Q000235:genetics / Q000378:metabolism*; D024642:Potassium Channels, Voltage-Gated; D019076:Transgenes / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D051638:Ether-A-Go-Go Potassium Channels; C092509:KCNH6 protein, human; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; C059983:potassium channel protein I(sk); D011188:Potassium