Upregulation of K2P3.1 K+ Current Causes Action Potential Shortening in Patients with Chronic Atrial Fibrillation
Background—Antiarrhythmic management of atrial fibrillation (AF) remains a major clinical challenge. Mechanism-based approaches to AF therapy are sought to increase effectiveness and to provide individualized patient care. K2P3.1 (TASK-1) two-pore-domain K+ (K2P) channels have been implicated in action potential regulation in animal models. However, their role in the pathophysiology and treatment of paroxysmal and chronic AF patients is unknown.
Methods and Results—Right and left atrial tissue was obtained from patients with paroxysmal (p) or chronic (c)AF and from sinus rhythm (SR) controls. Ion channel expression was analyzed by quantitative real-time PCR and Western blot. Membrane currents and action potentials were recorded using voltage- and current-clamp techniques. K2P3.1 subunits exhibited predominant atrial expression, and atrial K2P3.1 transcript levels were highest among functional K2P channels. K2P3.1 mRNA and protein levels were increased in cAF. Enhancement of corresponding currents in the right atrium resulted in shortened action potential duration at 90% of repolarization (APD90) compared to patients in SR. By contrast, K2P3.1 expression was not significantly affected in pAF subjects. Pharmacological K2P3.1 inhibition prolonged APD90 in atrial myocytes from cAF patients to values observed among SR subjects.
Conclusions—Enhancement of atrial-selective K2P3.1 currents contributes to APD shortening in cAF patients, and K2P3.1 channel inhibition reverses AF-related APD shortening. These results highlight the potential of K2P3.1 as a novel drug target for mechanism-based AF therapy.
- Received August 5, 2014.
- Revision received April 29, 2015.
- Accepted May 1, 2015.