Transgenic upregulation of IK1 in mice led to multiple abnormalities of cardiac excitability, including slowed heart rate, premature ventricular contractions, AV block, and atrial fibrillation.
Transgenic upregulation of IK1 in mice leads to significant adverse effects on cardiac electrical activity, including shortened action potential duration, short Q-T interval, and arrhythmias.
To assess the functional significance of upregulation of the cardiac current (IK1), we have produced and characterized the first transgenic (TG) mouse model of IK1 upregulation. To increase IK1 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 100%. In adult ventricular myocytes expressing the Kir2.1-GFP subunit, IK1 conductance at the reversal potential was increased approximately 9- and approximately 10-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 IK1 upregulation, confirms the significant role of IK1 in cardiac excitability, and is consistent with adverse effects of IK1 upregulation on cardiac electrical activity.
Li et al. (2004) studied Cardiac excitability abnormalities. Transgenic upregulation of IK1 (Kir2.1 expression) was evaluated on Cardiac excitability and electrical activity. Transgenic upregulation of IK1 in mice led to multiple abnormalities of cardiac excitability, including slowed heart rate, premature ventricular contractions, AV block, and atrial fibrillation.