Abstract 19574: Overexpression of Active Katp Channels in Adult Mouse Hearts Leads to Conduction Block and Heart Failure

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ATP-sensitive potassium (KATP) channels are hetero-octamers of four inward rectified potassium channel subunits (Kir6.1 or Kir6.2) with four sulfonylurea receptor subunits (SUR1 or SUR2). Cardiac sarcolemmal KATP channels are normally closed by high intracellular ATP concentration and will activate under severe pathological conditions where intracellular ATP depletes. Double transgenic mice overexpressing both ATP-insensitive Kir6.2 [K185Q, ΔN30] and SUR1 have shown arrhythmia and premature death. The premature death prevented further investigation of the underlying mechanism. In the present study, the tamoxifen (Tx)-inducible Cre-ER system was introduced to control timing of Kir6.2 [K185Q, ΔN30] expression. Transgenic mice carrying αMHC-Cre-SUR1 were cross-bred with mice carrying myh6-Cre-ER and Rosa26-Kir6.2 [K185Q, ΔN30] (a loxP-flanked DNA STOP sequence was inserted before Kir6.2 transgene). Adult triple transgenic (TTG) as well as littermate double transgenic (DTG), single transgenic (STG), and wild type (WT) mice were injected with Tx and conscious ECG recordings were monitored daily. Prior to Tx induction, SUR1 overexpressing mice have a prolonged PR interval. Within one week after Tx induction, TTG mice show further PR prolongation progressing to 2° AV block and occasionally AV dissociation. TTG mice also displayed severe bradycardia and morphological changes in the ST segment, which were not observed in littermate DTG, STG or WT mice. Two weeks after Tx induction, TTG mice developed larger hearts (wet heart weight: tibia length of 8.9 vs. 7.7 mg/mm in SUR1 expressing mice, p<0.05) and over half of the TTG mice developed edema throughout the body. TTG mice also showed higher mortality following induction (10 of 23 TTG deaths vs. 1 of 35 in littermates). H & E staining of heart slices revealed larger intercellular volume in TTG but not in littermates. These results suggest that overexpression of both active KATP subunits in adult hearts leads to conduction block, possible alterations in repolarization patterns, heart failure, and higher mortality. This model reiterates and further defines the severe pathology of overactive myocardial KATP channels and now provides the necessary system in which to dissect the mechanistic basis.