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* To whom correspondence should be addressed. E-mail: alopatin{at}umich.edu.
To assess the functional significance of up-regulation of the cardiac current, IK1, we have produced and characterized a first transgenic mouse model of IK1 up-regulation. To increase IK1 density, a pore forming subunit of Kir2.1 (GFP-tagged) channel was expressed in the heart under control of the 
-myosin heavy chain promoter. Two lines of transgenic animals were established with a high level of transgene 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 <=1 month old heart weight/ body weight ratio was increased by more than 100%. In adult ventricular myocytes expressing Kir2.1-GFP subunit, IK1 conductance at the reversal potential was increased ~9 and ~10 fold in lines 1 and 2, respectively. Expression of 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, AV block, and atrial fibrillation. Line 1 mice displayed a less severe phenotype. In both transgenic lines: (i) APD90, MAP75-90 were significantly reduced leading to neuron like APs, and (ii) the slow phase of T wave was abolished leading to a short QT interval. This study provides a new transgenic model of IK1 up-regulation, confirms the significant role of IK1 in cardiac excitability, and is consistent with IK1 up-regulation having adverse effects on cardiac electrical activity.
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