Transgenic upregulation of IK1 in the mouse heart leads to multiple abnormalities of cardiac excitability

To assess the functional significance of upregulation of the cardiac current (I-K1), we have produced and characterized the first transgenic (TG) mouse model of I-K1 upregulation. To increase I-K1 density, a pore-forming subunit of the Kir2.1 ( green fluorescent protein-tagged) channel was expressed in the heart under control of the alpha-myosin heavy chain promoter. Two lines of TG animals were established with a high level of TG expression in all major parts of the heart: line 1 mice were characterized by 14% heart hypertrophy and a normal life span; line 2 mice displayed an increased mortality rate, and in mice less than or equal to1 mo old, heart weight-to-body weight ratio was increased by >100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, I-K1 conductance at the reversal potential was increased similar to9- and similar to10-fold in lines 1 and 2, respectively. Expression of the Kir2.1 transgene in line 2 ventricular myocytes was heterogeneous when assayed by single-cell analysis of GFP fluorescence. Surface ECG recordings in line 2 mice revealed numerous abnormalities of excitability, including slowed heart rate, premature ventricular contractions, atrioventricular block, and atrial fibrillation. Line 1 mice displayed a less severe phenotype. In both TG lines, action potential duration at 90% repolarization and monophasic action potential at 75-90% repolarization were significantly reduced, leading to neuronlike action potentials, and the slow phase of the T wave was abolished, leading to a short Q-T interval. This study provides a new TG model of I-K1 upregulation, confirms the significant role of I-K1 in cardiac excitability, and is consistent with adverse effects of I-K1 upregulation on cardiac electrical activity.