title: Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha(3)-isoform in hearts.
abstract: To understand why the adult human heart expresses three isoforms of the sodium pump, we generated transgenic mice (TGM) with 2.3- to 5. 5-fold overexpression of the human alpha(3)-isoform of Na-K-ATPase in the heart. Hearts from the TGM had increased maximal Na-K-ATPase activity and ouabain affinity compared with control hearts, even though the density of Na-K-ATPase pump sites (of all isoforms) was similar to that of control mice. In perfused hearts, contractility both at baseline and in the presence of ouabain tended to be greater in TGM than in controls. Surface electrocardiograms in anesthetized TGM had a steeper dependence of Q-T on sinus cycle length, and Q-T intervals measured during atrial pacing were significantly longer in TGM. Q-T dispersion during sinus rhythm also tended to be longer in TGM. Thus TGM overexpressing human alpha(3)-isoform have several of the phenotypical features of human long Q-T syndrome, despite the absence of previously described mutations in Na(+) or K(+) channels.
authors.affiliation: Departments of Internal Medicine and Pediatrics, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: O'Brien
authors.forename: M
authors.initials: M
authors.lastname: Apkon
authors.forename: C I
authors.initials: CI
authors.lastname: Berul
authors.forename: H T
authors.initials: HT
authors.lastname: Patel
authors.forename: K
authors.initials: K
authors.lastname: Saupe
authors.forename: M
authors.initials: M
authors.lastname: Spindler
authors.forename: J S
authors.initials: JS
authors.lastname: Ingwall
authors.forename: R
authors.initials: R
authors.lastname: Zahler
mesh_terms: D000818:Animals; D002304:Cardiac Pacing, Artificial; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004562:Electrocardiography / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000096:biosynthesis / Q000235:genetics; D016014:Linear Models; D008133:Long QT Syndrome / Q000201:enzymology* / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000187:drug effects / Q000235:genetics; D009206:Myocardium / Q000201:enzymology*; D010042:Ouabain / Q000494:pharmacology; D010641:Phenotype; D000254:Sodium-Potassium-Exchanging ATPase / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics; D017180:Tachycardia, Ventricular / Q000209:etiology
chemical_list: D004791:Enzyme Inhibitors; D007527:Isoenzymes; D010042:Ouabain; D000254:Sodium-Potassium-Exchanging ATPase