Phenotypical features of long Q-T syndrome in transgenic mice expressing human Na-K-ATPase alpha(3)-isoform in hearts

To understand why the adult human heart expresses three isoforms of the sod ium pump, we generated transgenic mice (TGM) with 2.3- to 5.5-fold overexpr ession of the human alpha (3)-isoform of Na-K-ATPase in the heart. Hearts f rom 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 he arts, contractility both at baseline and in the presence of ouabain tended to be greater in TGM than in controls. Surface electrocardiograms in anesth etized TGM had a steeper dependence of Q-T on sinus cycle length, and Q-T i ntervals 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 fea tures of human long Q-T syndrome, despite the absence of previously describ ed mutations in Na+ or K+ channels.