Distinct gene-specific mechanisms of arrhythmia revealed by cardiac gene transfer of two long QT disease genes, HERG and KCNE1

The long QT syndrome (LQTS) is a heritable disorder that predisposes to sud den cardiac death. LQTS is caused by mutations in ion channel genes includi ng HERG and KCNE1, but the precise mechanisms remain unclear. To clarify th is situation we injected adenoviral vectors expressing wild-type or LQT mut ants of HERG and KCNE1 into guinea pig myocardium, End points at 48-72 h in cluded electrophysiology in isolated myocytes and electrocardiography in vi vo. HERG increased the rapid component, I-Kr, of the delayed rectifier curr ent, thereby accelerating repolarization. increasing refractoriness, and di minishing beat-to-beat action potential variability. Conversely, HERG-G628S suppressed I-Kr without significantly delaying repolarization, Nevertheles s, HERG-G628S abbreviated refractoriness and increased beat-to-beat variabi lity, leading to early afterdepolarizations (EADs), KCNE1 increased the slo w component of the delayed rectifier, I-Ks, without clear phenotypic sequel ae, In contrast, KCNE1-D76N suppressed I-Ks and markedly slowed repolarizat ion, leading to frequent EADs and electrocardiographic QT prolongation. Thu s, the two genes predispose to sudden death by distinct mechanisms: the KCN E1 mutant flagrantly undermines cardiac repolarization, and HERG-G628S subt ly facilitates the genesis and propagation of premature beats. Our ability to produce electrocardiographic: long QT in vivo with a clinical KCNE1 muta tion demonstrates the utility of somatic gene transfer in creating genotype -specific disease models.