Trigger-Specific Remodeling of KCa2 Potassium Channels in Models of Atrial Fibrillation
Ann‐Kathrin Rahm, Dominik Gramlich, Teresa Wieder, Mara Elena Müller, Axel Schoeffel, Fadwa A. El Tahry, Patrick Most, Tanja Heimberger, Steffi Sandke, Tanja Weis, Nina D. Ullrich, Thomas Korff, Patrick Lugenbiel, Hugo A. Katus, Dierk Thomas
Abstract
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