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Titolo:
Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1
Autore:
Hoppe, UC; Marban, E; Johns, DC;
Indirizzi:
Johns Hopkins Univ, Inst Mol Cardiobiol, Baltimore, MD 21205 USA Johns Hopkins Univ Baltimore MD USA 21205 iobiol, Baltimore, MD 21205 USA
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 9, volume: 98, anno: 2001,
pagine: 5335 - 5340
SICI:
0027-8424(20010424)98:9<5335:DGMOAR>2.0.ZU;2-R
Fonte:
ISI
Lingua:
ENG
Soggetto:
RECTIFIER K+-CURRENT; CURRENT I-KR; POTASSIUM CHANNEL; EARLY AFTERDEPOLARIZATIONS; VENTRICULAR MYOCYTES; TRANSGENIC MICE; HEART-RATE; MUTATIONS; EXPRESSION; REPOLARIZATION;
Keywords:
adenovirus; long QT syndrome; in vivo;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
56
Recensione:
Indirizzi per estratti:
Indirizzo: Marban, E Johns Hopkins Univ, Inst Mol Cardiobiol, Ross 844,720 Rutland Ave, Baltimore, MD 21205 USA Johns Hopkins Univ Ross 844,720 Rutland Ave Baltimore MD USA 21205
Citazione:
U.C. Hoppe et al., "Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1", P NAS US, 98(9), 2001, pp. 5335-5340

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 abilityto produce electrocardiographic: long QT in vivo with a clinical KCNE1 mutation demonstrates the utility of somatic gene transfer in creating genotype-specific disease models.

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Documento generato il 24/09/20 alle ore 23:33:59