Trigger-Specific Remodeling of K_Ca2 Potassium Channels in Models of Atrial Fibrillation

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_Ca2.1-2.3 channel remodeling in atrial cells.

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.

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_Ca2.1 were linked to stretch and β-adrenergic stimulation. Furthermore, KCNN3/K_Ca2.3 expression was suppressed upon tachypacing and hypoxia. Finally, KCNN2/K_Ca2.2 abundance was specifically enhanced by hypoxia.

Reduction of K_Ca2.1-2.3 channel expression might contribute to the action potential prolongation in AF complicated by HF. Subtype-specific K_Ca2 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_Ca2 regulation in atrial myocytes provides a starting point for mechanism-based antiarrhythmic therapy.