Trigger-Specific Remodeling of KCa2 Potassium Channels in Models of Atrial Fibrillation

Aim: Effective antiarrhythmic treatment of atrial fibrillation (AF) constitutes a major challenge, in particular, when concomitant heart failure (HF) is present. HF-associated atrial arrhythmogenesis is distinctly characterized by prolonged atrial refractoriness. Small-conductance, calcium-activated K + (K Ca , SK, KCNN ) channels contribute to cardiac action potential repolarization and are implicated in AF susceptibility and therapy. The mechanistic impact of AF/HF-related triggers on atrial K Ca channels is not known. We hypothesized that tachycardia, stretch, β-adrenergic stimulation, and hypoxia differentially determine K Ca 2.1– 2.3 channel remodeling in atrial cells. Methods: KCNN1-3 transcript levels were assessed in AF/HF patients and in a pig model of atrial tachypacing-induced AF with reduced left ventricular function. HL-1 atrial myocytes were subjected to proarrhythmic triggers to investigate the effects on Kcnn mRNA and K Ca channel protein. Results: Atrial KCNN1-3 expression was reduced in AF/HF patients. KCNN2 and KCNN3 suppression was recapitulated in the corresponding pig model. In contrast to human AF, KCNN1 remained unchanged in pigs. Channel- and stressor-specific remodeling was revealed in vitro. Lower expression levels of KCNN1 /K Ca 2.1 were linked to stretch and β-adrenergic stimulation. Furthermore, KCNN3 /K Ca 2.3 expression was suppressed upon tachypacing and hypoxia. Finally, KCNN2 /K Ca 2.2 abundance was specifically enhanced by hypoxia. Conclusion: Reduction of K Ca 2.1– 2.3 channel expression might contribute to the action potential prolongation in AF complicated by HF. Subtype-specific K Ca 2 channel remodeling induced by tachypacing, stretch, β-adrenergic stimulation, or hypoxia is expected to differentially determine atrial remodeling, depending on patient-specific activation of each triggering factor. Stressor-dependent K Ca 2 regulation in atrial myocytes provides a starting point for mechanism-based antiarrhythmic therapy. Keywords: atrial fibrillation, calcium, K Ca channel, KCNN , remodeling, SK channel