Inward Rectifier K Currents Contribute to the Proarrhythmic Electrical Phenotype of Atria Overexpressing Cyclic Adenosine Monophosphate Response Element Modulator Isoform CREM-IbΔC-X.

BACKGROUND Transgenic mice (TG) with heart-directed overexpresion of the isoform of the transcription factor cyclic adenosine monophosphate response element modulator (CREM), CREM-IbΔC-X, display spontaneous atrial fibrillation (AF) and action potential prolongation. The remodeling of the underlying ionic currents remains unknown. Here, we investigated the regulatory role of CREM-IbΔC-X on the expression of K channel subunits and the corresponding K currents in relation to AF onset in TG atrial myocytes. METHODS AND RESULTS ECG recordings documented the absence or presence of AF in 6-week-old (before AF onset) and 12-week-old TG (after AF onset) and wild-type littermate mice before atria removal to perform patch clamp, contractility, and biochemical experiments. In TG atrial myocytes, we found reduced repolarization reserve K currents attributed to a decrease of transiently outward current and inward rectifier K current with phenotype progression, and of acetylcholine-activated K current, age independent. The molecular determinants of these changes were lower mRNA levels of , , , and and decreased protein levels of K channel interacting protein 2 (KChIP2 ), Kir2.1/3, and Kir3.1/4, respectively. After AF onset, inward rectifier K current contributed less to action potential repolarization, in line with the absence of outward current component, whereas the acetylcholine-induced action potential shortening before AF onset (6-week-old TG mice) was smaller than in wild-type and 12-week-old TG mice. Atrial force of contraction measured under combined vagal-sympathetic stimulation revealed increased sensitivity to isoprenaline irrespective of AF onset in TG. Moreover, we identified , , , and as novel CREM-target genes. CONCLUSIONS Our study links the activation of cyclic adenosine monophosphate response element-mediated transcription to the proarrhythmogenic electrical remodeling of atrial inward rectifier K currents with a role in action potential duration, resting membrane stability, and vagal control of the electrical activity.